Cytokine profile of protective anti-Trichinella spiralis CD4+ OX22− and non-protective CD4+ OX22+ thoracic duct cells in rats: secretion of IL-4 alone does not determine protective capacity

We analysed the cytokine profile of a T cell subset (CD4⁺ CD45 RC⁻) that confers protection against Trichinella spiralis infection in rats. These CD4⁺ cells are generated in the gut and appear in the thoracic duct lymph within 72 h after infection. Cytokine mRNA levels for IL-2, IL-3, IL-4, IL-5, IL-10 and IFN-γ and functional cytokine secretion for IL-4, IL-5, IFN-γ, TNF-α and mast cell differentiation activity were tested in vitro following stimulation with T. spiralis antigens. Compared to a non-protective T cell population (CD4⁺ CD45 RC⁺ or CD8⁺), also isolated from the same thoracic lymph, no significant differences were observed in the levels of mRNA for IL-2, IL-3, IL-4, IL-5, IL-10 or IFN-γ in the protective CD4⁺ CD45 RC⁻ cells. However, analysis of the cytokine activities in culture supernatant of these T cell subsets following 24 h stimulation in vitro with T. spiralis antigens showed that significant IL-4 and IL-5 activity but little IFN-γ or TNF-α was secreted by the protective CD4⁺ CD45 RC⁻ cells. Whereas the non-protective CD4⁺ CD45 RC⁺ cells secreted significant levels of IL-4, IFN-γ, mast cell differentiating activity and TNF-α but little IL-5 activity. Nonprotective CD8⁺ cells were found to secrete IL-4 but not IL-5. Production of IL-4 was essentially equal for both protective and non-protective T cell subsets. These findings suggest that the presence or absence of IFN-γ secretion, rather than IL-4 alone, determines whether a T cell subset has protective activity against T. spiralis infection in rats.     

Inflammatory infiltrate and interleukin-8 expression in the synovium of psoriatic arthritis – an immunohistochemical and mRNA analysis

Psoriatic arthritis is an inflammatory arthropathy that ultimately can lead to joint destruction. In this study, we investigated the immunophenotype of the inflammatory cells and the expression of interleukin-8 (IL-8), which is the hallmark chemoattractant cytokine of psoriasis in synovial membranes from patients exhibiting active psoriatic synovitis (n=9). The tissue samples were examined by immunohistochemistry, Western blot analysis and in situ hybridisation. The inflammatory infiltrate consisted predominantly of CD3⁺ T lymphocytes, with a higher proportion of CD4⁺ than CD8⁺ T lymphocytes in six cases. CD3⁺ T lymphocytes were focally distributed near small blood vessels and the enlarged synovial intima. CD1⁺ interdigitating reticulum cells were not detected. CD22⁺ B lymphocytes and plasma cells were found in small aggregates without KiM4⁺ follicular dendritic cells. KiM8⁺ macrophages were located in the synovial intima and were distributed in a diffuse pattern near the synovial lining cells. CD15⁺ neutrophil granulocytes were detected in four cases. They were preferentially located in the vicinity of blood vessels and the synovial intima. IL-8 was found at a high level in the synovial lining cells and to a lesser extent in cells located in the perivascular areas. Immunofluorescence double staining showed IL-8 to be expressed in KiM8⁺ multinucleated giant cells, KiM8⁺ macrophages and CD3⁺ T lymphocytes. IL-8 receptor A was demonstrated in the synovial lining and in macrophages and lymphocytes. IL-8 was detected by immunoblot analysis of the synovial tissue at 8.4 kD. Employing in situ hybridisation, IL-8 mRNA was strongly and preferentially expressed in the synovial intima, as well as in macrophages and lymphocytes. The immunophenotype of the psoriatic arthritis inflammatory cells shows great similarity to the inflammatory infiltrate found in the synovial tissue of patients with rheumatoid arthritis. The preferential expression of IL-8 and IL-8 mRNA in the enlarged synovial intima and in lymphocytes and macrophages suggests that IL-8 exerts its action through activated mononuclear cells and T lymphocytes. It seems to play a role in regulating leucocyte traffic into the enlarged synovial intima and may contribute to the aggressive synovitis of patients with psoriatic arthritis. Received: 14 August 1997 / Accepted: 25 August 1997     

Interleukin-10, interleukin-12, and tumor necrosis factor-α differentially influence the proliferation of human CD8+ and CD4+ T-cell clones

 Activation and proliferation of human T lymphocytes in vitro can be obtained by various stimuli including specific antigens, mitogens, and cytokines. Here we describe the effect of interleukin-10, interleukin-12 and tumor necrosis factor-α on the interleukin-2 dependent proliferation and function of established human CD4⁺ and CD8⁺ alloreactive T-cell clones in the absence of antigen presenting cells. IL-12 and TNF-α both demonstrated an inhibitory effect on the proliferation of CD8⁺ cytotoxic T lymphocyte clones, whereas IL-10 enhanced the proliferation. IL-12-induced inhibition of CD8⁺ CTL clones was not mediated by the endogenous production of TNF-α by these clones. The strong inhibitory effect of IL-12 and TNF-α did not result in apoptosis. These cytokines did not alter the cytotoxicity of CD8⁺ CTL clones. When CD4⁺ T-cell clones were tested in the absence of APC, no significant change in IL-2-dependent proliferation due to IL-10, IL-12, and TNF-α could be measured. Since these effects on established CTL clones are in contrast to the effects of IL-10, IL-12, and TNF-α during the induction phase of immune responses, a dichotomy of immunomodulatory cytokines such as IL-10, IL-12, and TNF-α early and late in the immune response is suggested. Received: 2 January 1996 / Accepted: 22 January 1996     

Impaired Mitogenic Response of Peripheral Blood T Cells in Ulcerative Colitis Is Not Due to Apoptosis

An abnormal immune response may play apathogenic role in ulcerative colitis (UC). Animalmodels suggest that T-cell regulation may be of centralimportance in the inflammatory process. Our aims werethe characterization of the phenotype andfunctional status of circulating T-cells in ulcerativecolitis patients and to determine if activation-inducedcell death in CD4⁺ and CD8⁺lymphocytes in patients differs from healthy controls.Forty-eight patients (24 women and 24 men) fulfillingthe histopathological, clinical, and immunologicalcriteria for UC were studied. T-cell phenotype andfunction were studied in blood lymphocytes from patientswith ulcerative colitis and healthy donors by flowcytometric analysis, as well as [³H]thymidineincorporation. There were no significant differences in the percentage of T-cell subpopulations(CD3, CD4, CD8) and NK cells in the different groups.The percentage of cells in growth phase S+G₂Mat two and three days of phytohemagglutinin (PHA) stimulation was significantly decreased in UCpatients, but the percentage of CD4⁺ andCD8⁺ cells in UC patients that showedapoptosis was not significantly different than that inthe control group. Proliferative responses to IL-4 also suggested that a reducedresponsiveness to this cytokine may be involved in UC.In conclusion, the impaired proliferative response toPHA of T lymphocytes from UC patients is not associated with an in vitro increase in theapoptotic response in CD4⁺ or CD8⁺cells. A reduced IL-4 response may be involved in thispeculiar mitogenic response. These changes may be pathogenic or a favorable adaptivemechanism.     

Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

Cancer/testis (CT) antigens represent prime candidates for immunotherapy in cancer patients, because their expression is restricted to cancer cells and germ cells of the testis. MAGE-C1/CT7 is a CT antigen that is highly expressed in several types of cancers. Spontaneous occurrence of CT7-specific antibodies was previously detected by SEREX screen in a melanoma patient. However, naturally occurring CT7-specific T-cell responses have thus far not been detected. Peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients expressing CT7 in their tumor lesions (CT7⁺) were analyzed for CT7-specific T-cell responses using overlapping peptides. CT7-specific CD4⁺ T-cell responses were detected in three patients (11.5%). These CT7-specific CD4⁺ T-cell responses were detectable in melanoma patients’ PBMCs exclusively from preexisting CD45RA⁻ memory CD4⁺ T-cell pool. Additional CT7-specific memory CD4⁺ T-cell responses were detected in CT7⁺ melanoma patients after depletion of CD4⁺CD25high Treg cells showing that Treg cells impact on CT7-specific CD4⁺ T cells in melanoma patients. CT7-specific CD4⁺ T-cell clones were generated and used to define minimal epitopes, restriction elements, and confirm the recognition of naturally processed antigen. Surprisingly, these clones were able to secrete perforin and exert cytotoxicity. This study shows that CT7 can induce specific cellular immunity in melanoma patients. Based on these findings, CT7 will be further explored as a potential vaccine for melanoma immunotherapy.     

Expansion of CD8+CD57+ T cells after allogeneic BMT is related with a low incidence of relapse and with cytomegalovirus infection

Summary. Peripheral blood lymphocytes of 46 recipients of lymphocyte-depleted bone marrow allografts were pheno-typically analysed over a period of 1 year. We investigated the repopulation of lymphocyte subpopulations and their relation with clinical parameters such as graft-versus-host disease (GVHD), graft-versus-leukaemia and cytomegalovirus (CMV) infection. The number of repopulated T cells varied strongly between the blood samples of the recipients. In 45% of the recipients the number of T cells recovered to or above normal levels within 3 months after bone marrow transplantation (BMT), whereas the other recipients remained below normal up to 1 year after BMT. In recipients with a high repopulation, the CD8⁺ T-cell subset contributed more to this high repopulation than the CD4⁺ T-cell subset. We showed that the majority of T cells of these recipients expressed the a/3 T-cell receptor, CD8, CD57 and CDllb. HLA-DR was also highly expressed reflecting the activation stage of T cells in these recipients. BMT recipients with a high repopulation of CD8⁺ T cells showed a lower incidence of leukaemic relapse than recipients with a low repopulation. The 3-year probability of relapse was 19% versus 64% (P=O03), respectively. The relative high number of CD8⁺ T cells at 3 months after BMT was not associated with the incidence of GVHD. In contrast, occurrence of CMV infection after BMT was significantly higher in these recipients. Our results indicate that CD8⁺ T cells, predominantly CD57⁺, of BMT recipients with an expansion of these cells represent an in vivo activated cell population. This CD8⁺ T-cell population may consist partially of cytotoxic cells with anti-leukaemic activity as suggested by a low relapse rate. The signal for the strong expansion of these CD8+CD57+ T cells after BMT is still unclear, but association with CMV infection suggests that viral antigens are involved.     

CD8-positive adult T-cell leukemia cells with an integrated defective HTLV-I genome show a paracrine growth to IL-2

We describe a 50-year-old man with adult T-cell leukemia complicated by laryngeal tuberculosis whose tumor cells proliferate in response to IL-2 in a paracrine manner. On admission, the patient's white blood cell count was 17,900/mm³; 73% were abnormal lymphocytes with convoluted nuclel. FACS analysis showed that the tumor cells were CD4-negative, CD8-positive T cells. Southern blot analysis of tumor cells revealed integration of a defective HTLV-I genome lacking gag and pol genes. He was diagnosed with chronic ATL complicated by laryngeal tuberculosis. The primary leukemic cells expressed IL-2Rα and IL-2Rβ detected by FACS and Northern blot analysis and showed marked growth in response to exogenously added recombinant IL-2 in short-term cultures. Northern blot analysis did not show any IL-2 mRNA. We have previously demonstrated that primary leukemic cells from some ATL patients grow in response to IL-2 in an autocrine or paracrine manner. These results suggest that in CD8 ATL, IL-2 may beinvolved in a paracrine manner. © 1994 Wiley-Liss, Inc.     

Effect of BSA Antigen Sensitization during the Acute Phase of Influenza A Viral Infection on CD11c+ Pulmonary Antigen Presenting Cells

BackgroundInfluenza A viral infection is concerned with induction of asthma. CD11c + pulmonary antigen presenting cells (APCs) play a central role in sensitization with inhaled antigens during the acute phase of influenza A viral infection and also reside on bronchial epithelium for the long term after sensitization. To investigate the role of CD11c + pulmonary APCs in the inhaled antigen sensitization during the acute phase of influenza A viral infection, we analyzed their function.MethodsMice were infected with influenza A virus and were sensitized intranasally with BSA/alum during the acute phase of influenza A viral infection. Expression of surface antigens on CD11c⁺ pulmonary APCs was analyzed by FACS. Cytokine production from CD11c⁺ pulmonary APCs, and interaction between CD11c⁺ pulmonary APCs and naive CD4⁺ T cells was assessed by ELISA. Ability of antigen presentation by CD11c⁺ pulmonary APCs was measured by proliferation assay.ResultsBSA antigen sensitization during the acute phase of influenza A viral infection induced eosinophil recruitment into the lungs after BSA antigen challenge and moderately increased expression of MHC class II molecules on CD11c⁺ pulmonary APCs. The interaction between the CD11c⁺ pulmonary APCs and naive CD4⁺ T cells secreted large amounts of IL-10.ConclusionsBSA antigen sensitization during the acute phase of influenza A viral infection enhanced IL-10 production from naive CD4⁺ T cell interaction with CD11c⁺ pulmonary APCs. The IL-10 secretion evoked Th2 responses in the lungs with downregulation of Th1 responses and was important for the eosinophil recruitment into the lungs after BSA antigen challenge.     

Detection of type 2-like T-helper cells in hepatitis C virus infection: Implications for hepatitis C virus chronicity

One striking clinical feature of hepatitis C virus (HCV) infection is that more than 50% of patients with acute hepatitis C will develop chronic infection. To investigate its possible mechanisms, we examined the activation of type 2-like T-helper (Th2-like) cells relating to the development of chronicity. Peripheral blood CD4⁺ T-cell proliferation and cytokine secretion in response to a panel of recombinant HCV antigens including core (C22), envelope 1 (E1), E2, nonstructural (NS) protein 4 (C100), fusion protein of NS3 and NS4 (C200), and NS5 were assayed in 17 patients with acute hepatitis C. All six patients with self-limited disease had a significant CD4⁺ T-cell proliferation to C22, E1, C100, C200, and NS5, running parallel with the antigen-stimulated secretion of interleukin (IL)-2 and interferon γ (IFN-γ), but not with interleukin (IL)-4 and IL-10, indicating predominant Th1 responses. Among the remaining 11 patients who developed chronicity, 6, 2, and 9 cases showed a specific CD4⁺ T-cell response to C22, C100, and C200, respectively, and the responses were significantly lower than those of cases with recovery in terms of stimulation index (SI) (P < .05) and of antigen-stimulated IL-2 and IFN-γ production. Importantly, IL-4 and IL-10 (Th2 responses) were detectable, and C22-specific Th2-like T-cell clones could be generated from patients with chronicity. The data suggested that activation of Th2 responses in acute hepatitis C patients may play a role in the development of chronicity.(Hepatology 1997 Feb;25(2):449-58)     

Enhanced SARS-CoV-2-Specific CD4+ T Cell Activation and Multifunctionality in Late Convalescent COVID-19 Individuals

Background: Examination of CD4⁺ T cell responses during the natural course of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection offers useful information for the improvement of vaccination strategies against this virus and the protective effect of these T cells. Methods: We characterized the SARS-CoV-2-specific CD4⁺ T cell activation marker, multifunctional cytokine and cytotoxic marker expression in recovered coronavirus disease 2019 (COVID-19) individuals. Results: CD4⁺ T-cell responses in late convalescent (>6 months of diagnosis) individuals are characterized by elevated frequencies of activated as well as mono, dual- and multi-functional Th1 and Th17 CD4⁺ T cells in comparison to early convalescent (<1 month of diagnosis) individuals following stimulation with SARS-CoV-2-specific antigens. Similarly, the frequencies of cytotoxic marker expressing CD4⁺ T cells were also enhanced in late convalescent compared to early convalescent individuals. Conclusion: Our findings from a low-to middle-income country suggest protective adaptive immune responses following natural infection of SARS-CoV-2 are elevated even at six months following initial symptoms, indicating the CD4⁺ T cell mediated immune protection lasts for six months or more in natural infection.     

Characterization of Lymphocytic Subsets and Cytokine Production in Gastric Biopsy Samples from Helicobacter pylori Patients

Background: This study characterized the phenotypic subsets of isolated gastric lymphocytes and the cellular immune response in cultured gastric biopsy specimens. Methods: Endoscopy specimens from 40 Helicobacter pylori-positive and 40 H. pylori-negative patients were studied. a) Isolated gastric lymphocytes were analysed for CD4⁺, CD8⁺ T-lymphocyte subsets, activated T cells, and natural killer cells on a fluorescence-activated cell sorter, using monoclonal antibodies. b) The supernatant of cultured gastric biopsy specimens were assayed for interleukin (IL)-2, IL-4, and IL-6 levels. Results: In H. pylori-positive patients there was (a) a decrease in CD4⁺/CD8⁺ T cells, no change in activated T cells, and an increase in natural killer cells, and (b) no change in IL-2 levels and a significant increase in IL-4 and IL-6 levels. Conclusions: There is an increase in CD8⁺ lymphocytes and natural killer cells, and the observed increase in IL-4 and IL-6 might be important in H. pylori-associated gastritis.     

CD3?CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder

The CD3⁻CD4⁺ lymphoid variant of hypereosinophilic syndrome is characterized by hypereosinophilia and clonal circulating CD3⁻CD4⁺ T cells. Peripheral T-cell lymphoma has been described during this disease course, and we observed in our cohort of 23 patients 2 cases of angio-immunoblastic T-cell lymphoma. We focus here on histopathological (n=12 patients) and immunophenotypic (n=15) characteristics of CD3⁻CD4⁺ lymphoid variant of hypereosinophilic syndrome. Atypical CD4⁺ T cells lymphoid infiltrates were found in 10 of 12 CD3⁻CD4⁺ L-HES patients, in lymph nodes (n=4 of 4 patients), in skin (n=9 of 9) and other extra-nodal tissues (gut, lacrymal gland, synovium). Lymph nodes displayed infiltrates limited to the interfollicular areas or even an effacement of nodal architecture, associated with proliferation of arborizing high endothelial venules and increased follicular dendritic cell meshwork. Analysis of 2 fresh skin samples confirmed the presence of CD3⁻CD4⁺ T cells. Clonal T cells were detected in at least one tissue in 8 patients, including lymph nodes (n=4 of 4): the same clonal T cells were detected in blood and in at least one biopsy, with a maximum delay of 23 years between samples. In the majority of cases, circulating CD3⁻CD4⁺ T cells were CD2^hi (n=9 of 14), CD5^hi (n=12 of 14), and CD7⁻(n=4 of 14) or CD7^low (n=10 of 14). Angio-immunoblastic T-cell lymphoma can also present with CD3⁻CD4⁺ T cells; despite other common histopathological and immunophenotypic features, CD10 expression and follicular helper T-cell markers were not detected in lymphoid variant of hypereosinophilic syndrome patients, except in both patients who developed angio-immunoblastic T-cell lymphoma, and only at T-cell lymphoma diagnosis. Taken together, persistence of tissular clonal T cells and histopathological features define CD3⁻CD4⁺ lymphoid variant of hypereosinophilic syndrome as a peripheral indolent clonal T-cell lymphoproliferative disorder, which should not be confused with angio-immunoblastic T-cell lymphoma.     

CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes

Fibrocytes are collagen-type-I-producing cells that arise at low frequency from hematopoietic cells. We have analyzed in mice which leukocyte subsets are required for generation of fibrocytes and show that murine fibrocytes develop from the subpopulation of CD11b⁺ CD115⁺ Gr1⁺ monocytes under the control of CD4⁺ T cells. In the absence of CD4⁺ T cells, differentiation of fibrocytes was markedly reduced in vitro and in vivo. In the presence of CD4⁺ T cells, the characteristics of T-cell activation critically determined development of fibrocytes. Polyclonal activation of CD4⁺ T cells induced the release of soluble factors that completely prevented the outgrowth of fibrocytes and could be identified as IL-2, TNF, IFN-γ, and IL-4. Application of IL-2 and TNF significantly reduced the appearance of fibrocytes and the severity of fibrosis in the model of unilateral ureteral obstruction. In contrast, activation of CD4⁺ T cells in the presence of calcineurin inhibitors, but not mTOR inhibitors, markedly enhanced the outgrowth of fibrocytes and renal deposition of collagen I. Taken together, we show that differentiation of fibrocytes is critically dependent on CD4⁺ T cells and that the context of T-cell activation determines whether development of fibrocytes is supported or blocked. Our data may have implications for prevention of organ fibrosis in autoimmune diseases and transplantation.     

Augmented human-tumor-cytolytic activity of peripheral blood lymphocytes and cells from a mixed lymphocyte/tumor culture activated by interleukin-12 plus interleukin-2, and the phenotypic characterization of the cells in patients with advanced carcinoma

In this study, we evaluated the ability of combination regimens of interleukin-12 (IL-12) and interleukin-2 (IL-2) to induce effective killer cells against human tumors in vitro, in peripheral blood lymphocytes (PBL) from 15 cancer patients and mixed lymphocyte/tumor culture (MLTC) cells from 16 cancer patients, and carried out a phenotypic analysis of the cells responsible for the lysis of the human tumors. The freshly prepared PBL were cultivated with IL-2 alone or IL-12/IL-2 for 10 days [lymphokine-activated killer (LAK) cell generation system]. The MLTC cells (PBL cultured with mitomycin-C-treated allogeneic G-415 tumor cells for 3 days) were further cultivated with IL-2 or IL-12/IL-2 for 7 days [cytotoxic T lymphocytes (CTL) generation system]. The cytolytic activities of the lymphoid cells cultivated with IL-12/IL-2 were significantly augmented in both the LAK and CTL generation systems, as compared with those of cells treated with IL-2 alone. In the LAK generation system, the cytolytic activities of the cells cultivated with IL-12/IL-2 were significantly decreased by the method of negative selection of CD11b⁺ or CD56⁺ cells using immunomagnetic beads. The CD8⁺-depleted cells showed a slight decrease of activity. The killer cell activities of the CD4⁺-depleted cells remained unchanged. In the CTL generation system, the activity was markedly reduced by the elimination of the CD8⁺ or CD11b⁺ or CD56⁺ cells. The combined data suggested that IL-12/IL-2-induced killer effector cells in the LAK generation system were mainly of the natural killer (NK) type, comprising CD8^–CD11b⁺, CD8^– CD16b^–, CD3^–CD56⁺, and partly possible CD8⁺ CD11b^–T cells. CD8⁺ CD11b^–T cells mixed with cells of the NK type, comprising CD8^–CD11b⁺, CD8^– CD16b^– and CD3^–CD56⁺ cells, were the population of killer effector cells induced by IL-12/IL-2 in the CTL generation system.Abbreviations IL interleukin - LAK lymphokine-activated killer - CTL cytotoxic T lymphocytes - PBL peripheral blood lymphocytes - NK natural killer - MLTC mixed lymphocyte/tumor cell culture - TIL tumor-infiltrating lymphocytes     

Cytokine Profiles Contribute to Understanding the Pathogenic Difference Between Good Syndrome and Oral Lichen Planus: Two Case Reports and Literature Review

We described and analyzed the pathogenic difference between Good syndrome (GS) and oral lichen planus (OLP) in oral mucosa.Good syndrome (GS) is a rare disease characterized by B and T cell immunodeficiency associated with hypogammaglobulinemia and thymoma. GS patients frequently develop oral lichenoid lesions with lymphocytic infiltration beneath the basal layer. Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa characterized by destruction of basal cells by Langerhans cells, macrophages, and T lymphocytes. Although the histological features of the lesions of both diseases are very similar, the pathogenesis of GS in the oral mucosa remains unknown. In this study, we thus investigated the expression of infiltrating lymphocyte subsets (CD3, CD20, CD4, and CD8) and T helper (Th) cytokines including interferon (IFN)-γ (Th1 type), interleukin (IL)-4 (Th2 type), IL-17 (Th17 type), and IL-10 (regulatory T cell type) by immunohistochemistry in buccal mucosa specimens from 2 GS patients compared with 15 OLP patients. All patients showed a predominance of CD3⁺ T cells over CD20⁺ B cells, and CD4⁺ Th cells over CD8⁺ cytotoxic T cells. This polarization was especially prominent in GS. IFN-γ and IL-10 were strongly detected in the infiltrating lymphocytes of all patients. However, IL-4 and IL-17 were detected in OLP patients only.These results suggest that the pathogenesis of GS is different from that of OLP. GS is a unique inflammatory disorder characterized by dysfunction of Th2 and Th17 immune reactions via abnormal T–B cell interaction.     

High and Sustained Ex Vivo Frequency but Altered Phenotype of SARS-CoV-2-Specific CD4+ T-Cells in an Anti-CD20-Treated Patient with Prolonged COVID-19

Here, we longitudinally assessed the ex vivo frequency and phenotype of SARS-CoV-2 membrane protein (aa145–164) epitope-specific CD4⁺ T-cells of an anti-CD20-treated patient with prolonged viral positivity in direct comparison to an immunocompetent patient through an MHC class II DRB1*11:01 Tetramer analysis. We detected a high and stable SARS-CoV-2 membrane-specific CD4⁺ T-cell response in both patients, with higher frequencies of virus-specific CD4⁺ T-cells in the B-cell-depleted patient. However, we found an altered virus-specific CD4⁺ T-cell memory phenotype in the B-cell-depleted patient that was skewed towards late differentiated memory T-cells, as well as reduced frequencies of SARS-CoV-2-specific CD4⁺ T-cells with CD45RA⁻ CXCR5⁺ PD-1⁺ circulating T follicular helper cell (cT_FH) phenotype. Furthermore, we observed a delayed contraction of CD127⁻ virus-specific effector cells. The expression of the co-inhibitory receptors TIGIT and LAG-3 fluctuated on the virus-specific CD4⁺ T-cells of the patient, but were associated with the inflammation markers IL-6 and CRP. Our findings indicate that, despite B-cell depletion and a lack of B-cell—T-cell interaction, a robust virus-specific CD4⁺ T-cell response can be primed that helps to control the viral replication, but which is not sufficient to fully abrogate the infection.     

The role of Tα1 on the infective patients after hematopoietic stem cell transplantation

The present study was designed to investigate the effect of thymosin α1 (Tα1) administration in infective recipients of hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. Eight patients were enrolled in our study, including seven allo-HSCT patients and one auto-HSCT patient. These patients were allocated randomly into the treatment group (four cases) and control group (four cases). Tα1 was used in the treatment group to test its effectiveness in infection control. The concentrations of cytokines IFN-γ, IL-2, IL-4, IL-10, and IL-12 were observed, and the levels of CD3⁺, CD4⁺, and CD8⁺ T cells, as well as of CD4⁺/CD8⁺ and CD4⁺/CD25⁺ regulatory T cell (Treg) were measured. When Tα1 was administered for 2 weeks, the concentrations of these cytokines were increased after 1 month in the treatment group. Interestingly, the levels of IFN-γ, IL-2, IL-10, and IL-12 were increased in the treatment group more than those in the control group, whereas there were no significant differences between the treatment and control group in the levels of CD3⁺, CD4⁺, and CD8⁺ T cells, or in CD4⁺/CD8⁺ or CD4⁺/CD25⁺ Treg cells. Notably, Tα1 administration did not cause acute or chronic graft versus host disease (GVHD). We conclude that Tα1 administration is safe and may impact favorably on immune function, and that it may improve resistance to infection and induce immunotolerance without GVHD.     

The role of CD4+ and CD8+ T cells in protective immunity to the murine nematode parasite Trichuris muris

The role ofCD4⁺ and CD8⁺ T cells in protective immunity to Trichuris muris was studied in CD4⁺ or CD8⁺ or both CD4⁺ and CD8⁺ T cell-depleted BALB/c mice. To assess in vivo depletion of T-cell subsets, CD4⁺ and CD8⁺ T cells in the Peyer's patches, the mesenteric lymph nodes (MLN), and the spleens of mice treated with T cell-specific monoclonal antibodies (MoAbs) were analysed by FACS. CD4⁺ T cells were selectively depleted in mice injected with anti-CD4 MoAb i.p. and injection of anti-CD8 MoAb resulted in selective depletion ofCD8⁺ T cells. The expulsion ofl. muris was inhibited in CD4⁺ T cell-depleted mice and numerous worms were detected in the large intestine on days 14 and 21 after infection, although no suppression of protective immunity to T. muris was observed in CD8⁺ T cell-depleted mice. Moreover, there was no difference in suppression of protective immunity to T. muris between CD4⁺ T cell-depleted and both CD4⁺ and CD8⁺ T cell-depleted mice. These results indicate that CD4⁺ T cells play a central role in protective immunity to T. muris infection.