Detection of IFNγ-Secreting CD4+ and CD8+ Memory T Cells in COVID-19 Convalescents after Stimulation of Peripheral Blood Mononuclear Cells with Live SARS-CoV-2

Background: New coronavirus SARS-CoV-2, a causative agent of the COVID-19 pandemic, has been circulating among humans since November 2019. Multiple studies have assessed the qualitative and quantitative characteristics of virus-specific immunity in COVID-19 convalescents, however, some aspects of the development of memory T-cell responses after natural SARS-CoV-2 infection remain uncovered. Methods: In most of published studies T-cell immunity to the new coronavirus is assessed using peptides corresponding to SARS-CoV-1 or SARS-CoV-2 T-cell epitopes, or with peptide pools covering various parts of the viral proteins. Here, we determined the level of CD4⁺ and CD8⁺ memory T-cell responses in COVID-19 convalescents by stimulating PBMCs collected 1 to 6 months after recovery with sucrose gradient-purified live SARS-CoV-2. IFNγ production by the central and effector memory helper and cytotoxic T cells was assessed by intracellular cytokine staining assay and flow cytometry. Results: Stimulation of PBMCs with live SARS-CoV-2 revealed IFNγ-producing T-helper effector memory cells with CD4⁺CD45RA⁻CCR7⁻ phenotype, which persisted in circulation for up to 6 month after COVID-19. In contrast, SARS-CoV-2-specific IFNγ-secreting cytotoxic effector memory T cells were found at significant levels only shortly after the disease, but rapidly decreased over time. Conclusion: The stimulation of immune cells with live SARS-CoV-2 revealed a rapid decline in the pool of effector memory CD8⁺, but not CD4⁺, T cells after recovery from COVID-19. These data provide additional information on the development and persistence of cellular immune responses after natural infection, and can inform further development of T cell-based SARS-CoV-2 vaccines.     

Strong SARS-CoV-2 N-Specific CD8+ T Immunity Induced by Engineered Extracellular Vesicles Associates with Protection from Lethal Infection in Mice

SARS-CoV-2-specific CD8⁺ T cell immunity is expected to counteract viral variants in both efficient and durable ways. We recently described a way to induce a potent SARS-CoV-2 CD8⁺ T immune response through the generation of engineered extracellular vesicles (EVs) emerging from muscle cells. This method relies on intramuscular injection of DNA vectors expressing different SARS-CoV-2 antigens fused at their N-terminus with the Nef^mut protein, i.e., a very efficient EV-anchoring protein. However, quality, tissue distribution, and efficacy of these SARS-CoV-2-specific CD8⁺ T cells remained uninvestigated. To fill the gaps, antigen-specific CD8⁺ T lymphocytes induced by the immunization through the Nef^mut-based method were characterized in terms of their polyfunctionality and localization at lung airways, i.e., the primary targets of SARS-CoV-2 infection. We found that injection of vectors expressing Nef^mut/S1 and Nef^mut/N generated polyfunctional CD8⁺ T lymphocytes in both spleens and bronchoalveolar lavage fluids (BALFs). When immunized mice were infected with 4.4 lethal doses of 50% of SARS-CoV-2, all S1-immunized mice succumbed, whereas those developing the highest percentages of N-specific CD8⁺ T lymphocytes resisted the lethal challenge. We also provide evidence that the N-specific immunization coupled with the development of antigen-specific CD8⁺ T-resident memory cells in lungs, supporting the idea that the Nef^mut-based immunization can confer a long-lasting, lung-specific immune memory. In view of the limitations of current anti-SARS-CoV-2 vaccines in terms of antibody waning and efficiency against variants, our CD8⁺ T cell-based platform could be considered for a new combination prophylactic strategy.     

Peripheral Blood Immune Profiling of Convalescent Plasma Donors Reveals Alterations in Specific Immune Subpopulations Even at 2 Months Post SARS-CoV-2 Infection

Immune profiling of patients with COVID-19 has shown that SARS-CoV-2 causes severe lymphocyte deficiencies (e.g., lymphopenia, decreased numbers, and exhaustion of T cells) and increased levels of pro-inflammatory monocytes. Peripheral blood (PB) samples from convalescent plasma (CP) donors, COVID-19 patients, and control subjects were analyzed by multiparametric flow cytometry, allowing the identification of a wide panel of immune cells, comprising lymphocytes (T, B, natural killer (NK) and NKT cells), monocytes, granulocytes, and their subsets. Compared to active COVID-19 patients, our results revealed that the immune profile of recovered donors was restored for most subpopulations. Nevertheless, even 2 months after recovery, CP donors still had reduced levels of CD4⁺ T and B cells, as well as granulocytes. CP donors with non-detectable levels of anti-SARS-CoV-2-specific antibodies in their serum were characterized by higher Th9 and Th17 cells, which were possibly expanded at the expense of Th2 humoral immunity. The most noticeable alterations were identified in previously hospitalized CP donors, who presented the lowest levels of CD8⁺ regulatory T cells, the highest levels of CD56⁺CD16⁻ NKT cells, and a promotion of a Th17-type phenotype, which might be associated with a prolonged pro-inflammatory response. A longer follow-up of CP donors will eventually reveal the time needed for full recovery of their immune system competence.     

A potential immunopathogenic role for reduced IL-35 expression in allergic asthma

Objective: Allergic asthma is a chronic airway inflammation resulting from an imbalance of T helper (Th) cell responses to allergens. Interleukin (IL)-35 has been shown to have potent immunoregulatory properties. Whether IL-35 participates in the immunopathogenesis of allergic asthma patients is still unknown. Methods: CD4⁺ T cells and CD4⁺CD25^? T cells were obtained from peripheral blood mononuclear cells (PBMCs) using magnetic separation. The concentration of IL-35 in plasma was measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of the IL-35 subunits, EBI3 and IL-12p35, were detected by quantitative real-time PCR (qPCR). The proliferative responses of CFSE-labeled CD4⁺CD25^? T cells in the presence or absence of rhIL-35 were evaluated by flow cytometry. Cytokine production of activated CD4⁺CD25^? T cells was examined by flow cytometry and ELISA. Results: IL-35 protein and mRNA levels were decreased in allergic asthmatics. The frequencies of CD4⁺CD25⁺Foxp3⁺ Tregs and CD4⁺IL-12p35⁺ T cells in allergic asthma patients were lower than in healthy controls. Moreover, the addition of rhIL-35 suppressed CFSE⁺CD4⁺CD25^? T cell proliferation in vitro in a dose-dependent manner, and the suppression induced by rhIL-35 was associated with decreases in IL-4 but not IFN-γ and IL-17 production of activated CD4⁺CD25^? T cells. The increased level of Th1/Th2 was observed in allergic asthmatics in the presence of rhIL-35. Conclusions: Our data suggest that IL-35 can effectively suppress the proliferation and IL-4 production of activated CD4⁺CD25^? T cells in allergic asthma, and that IL-35 may be a new immunotherapy for asthma patients.     

Rudimentary signs of immunosenescence in Cytomegalovirus-seropositive healthy young adults

Ageing is associated with a decline in immune competence termed immunosenescence. In the elderly, this process results in an accumulation of differentiated ‘effector’ phenotype memory T cells, predominantly driven by Cytomegalovirus (CMV) infection. Here, we asked whether CMV also drives immunity towards a senescent profile in healthy young adults. One hundred and fifty-eight individuals (mean ± SD; age 21 ± 3 years, body mass index 22.7 ± 2.7 kg m²) were assessed for CMV serostatus, the numbers/proportions of CD4⁺ and CD8⁺ late differentiated/effector memory cells (i.e. CD27⁻CD28⁻/CD45RA⁺), plasma interleukin-6 (IL-6) and antibody responses to an in vivo antigen challenge (half-dose influenza vaccine). Thirty percent (48/158) of participants were CMV⁺. A higher lymphocyte and CD8⁺ count (both p < 0.01) and a lower CD4/CD8 ratio (p < 0.03) were observed in CMV⁺ people. Eight percent (4/58) of CMV⁺ individuals exhibited a CD4/CD8 ratio <1.0, whereas no CMV⁻ donor showed an inverted ratio (p < 0.001). The numbers of CD4⁺ and CD8⁺CD27⁻CD28⁻/CD45RA⁺ cells were ~ fourfold higher in CMV⁺ people (p < 0.001). Plasma IL-6 was higher in CMV⁺ donors (p < 0.05) and showed a positive association with the numbers of CD8⁺CD28⁻ cells (p < 0.03). Finally, there was a significant negative correlation between vaccine-induced antibody responses to the A/Brisbane influenza strain and CMV-specific immunoglobulin G titres (p < 0.05). This reduced vaccination response was associated with greater numbers of total CD8⁺ and CD4⁺ and CD8⁺CD27⁻CD28⁻/CD45RA⁺ cells (p < 0.05). This study observed marked changes in the immune profile of young adults infected with CMV, suggesting that this virus may underlie rudimentary aspects of immunosenescence even in a chronologically young population.     

Quantitative and functional analysis of core-specific T-helper cell and CTL activities in acute and chronic hepatitis B

Abstract: Aims/Background: CD4+ T-helper cell (Th) responses to hepatitis B virus (HBV) core antigen (HBc) are increased during exacerbations in acute and chronic hepatitis B (AHB, CHB) and might influence the induction of CD8+ cytotoxic T lymphocytes (CTL) that are important for viral clearance. Methods: HBc-specific proliferative responses and cytokine release of blood mononuclear cells (PBMC) were studied in patients with AHB or CHB, as well as responders and non-responders to interferon-α treatment (IFN-R, IFN-NR), by [³H]-thymidine-uptake, enzyme-linked immunosorbent assay (ELISA) and Elispot assay and were compared to peptide HBc18–27-specific CTL precursor frequencies among CD8+ T cells derived from HLA-A2+ patients. Results: HBc-specific proliferative PBMC responses and Th frequencies were significantly increased in AHB patients compared with untreated CHB patients. PBMC derived from IFN-R showed stronger cellular responses than IFN-NR. Stimulated PBMC from all patient groups secreted significantly more IFN-γ than IL-4 indicating Th1/Th0 cell responses. Furthermore, in AHB and IFN-R patients, high peptide HBc18–27-specific CTL precursor frequencies closely correlated with strong HBc-specific Th responses, whereas in untreated CHB and IFN-NR patients lower CTL frequencies were observed without correlation to Th activities. Conclusions: HBV core-specific Th-cell responses appeared to support efficient CTL induction in patients with viral clearance, whereas in chronic HBV carriers quantitatively insufficient Th and CTL responses were observed. This observation could be important for future therapeutic strategies.     

Probiotics increase T regulatory cells and reduce severity of experimental colitis in mice

AIM:To investigate the effect of probiotics on regulating T regulatory cells and reducing the severity of experimental colitis in mice. METHODS:Forty C57/BL mice were randomly divided into four groups.Colitis was induced in the mice using 2,4,6-trinitrobenzene sulfonic acid(TNBS).After 10-d treatment with Bifico capsules(combined bifidobacterium,lactobacillus and enterococcus),body weight,colonic weight,colonic weight index,length of colon,and histological scores were evaluated.CD4+CD25+Foxp3+T cell in mesenteric lymph nodes were measured by flow cytometry,and cytokines in colonic tissue homogenateswere analyzed by a cytometric bead array. RESULTS:The colonic weight index and the colonic weight of colitis mice treated with Bifico were lower than that of TNBS-induced mice without treatment. However,colonic length and percent of body weight amplification were higher than in TNBS-induced mice without treatment.Compared with TNBS-induced mice without treatment,the level of CD4+CD25+Foxp3+T cells in mesenteric lymph nodes,the expression of interleukin(IL)-2,IL-4 and IL-10 in colonic tissues from colitis mice treated with Bifico were upregulated,and tumor necrosis factor-αand interferon-γwere downregulated. CONCLUSION:Probiotics effectively treat experimental colitis by increasing CD4+CD25+Foxp3+T cell and regulating the balance of Th1 and Th2 cytokines in the colonic mucosa.     

Increased IL-4- and IL-17-producing CD8+ cells are related to decreased CD39+CD4+Foxp3+ cells in allergic asthma

Objective: In allergic asthma, regulatory T cell (Treg) number and function are decreased. Antigen-primed CD8⁺ T cells play an indispensable role in the full development of airway inflammation and airway hyper-responsiveness (AHR) occurring in asthma. In this study, we investigated the relationship between subpopulations of CD8⁺ T cells and CD39⁺ Tregs. Methods: Female C57BL/6 mice were used to develop the model of allergic asthma. Experimental mice were immunized with ovalbumin (OVA) by intra-peritoneal (i.p) injection and then challenged with OVA by intra-tracheal administration. Control mice were immunized with vehicle by i.p injection and challenged with OVA. Airway inflammation was determined by histology and AHR was measured by an invasive method. Levels of interferon (IFN)-γ, IL-4, and IL-17 in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay. The frequencies of CD8⁺IFN-γ⁺ cells (Tc1), CD8⁺IL-4⁺ cells (Tc2), CD8⁺IL-17⁺cells (Tc17), and CD39⁺Tregs were measured by flow cytometry. The correlation between CD39⁺Tregs and Tc subsets was analyzed by Pearson’s test. Results: Experimental mice displayed phenotypes of allergic asthma, including inflammatory cell infiltration into the lungs, goblet cell hyperplasia, increased airway resistance, and increased IL-4 and IL-17 in BALF. Compared to control mice, experimental mice displayed lower CD39⁺Tregs and Tc1 but higher Tc2 and Tc17. There was a negative correlation between CD39⁺Tregs and Tc2 or Tc17. Conclusion: In allergic asthma, increased Tc2 and Tc17 are possibly related to insufficient CD39⁺Tregs.     

Peripheral killer cells do not differentiate between asthma patients with or without fixed airway obstruction

Objective: The three main types of killer cells – CD8⁺ T cells, NK cells and NKT cells – have been linked to asthma and chronic obstructive pulmonary disease (COPD). However, their role in a small subset of asthma patients displaying fixed airway obstruction (FAO), similar to that seen in COPD, has not been explored. The objective of the present study was to investigate killer cell numbers, phenotype and function in peripheral blood from asthma patients with FAO, asthma patients without FAO, and healthy individuals. Methods: Peripheral CD8⁺ T cells (CD8⁺CD3⁺CD56^?), NK cells (CD56⁺CD3^?) and NKT-like cells (CD56⁺CD3⁺) of 14 asthma patients with FAO (post-bronchodilator FEV/FVC <0.7, despite clinician-optimised treatment), 7 asthma patients without FAO (post-bronchodilator FEV/FVC ≥ 0.7), and 9 healthy individuals were studied. Results: No significant differences were seen between the number, receptor expression, MAPK signalling molecule expression, cytotoxic mediator expression, and functional cytotoxicity of peripheral killer cells from asthma patients with FAO, asthma patients without FAO and healthy individuals. Conclusions: Peripheral killer cell numbers or functions do not differentiate between asthma patients with or without fixed airway obstruction.     

Increased susceptibility to oral Trichuris muris infection in the specific absence of CXCR5+ CD11c+ cells

Trichuris muris is a natural mouse helminth pathogen which establishes infection specifically in the caecum and proximal colon. The rapid expulsion of T. muris in resistant mouse strains is associated with the induction of a protective T helper cell type 2 (Th2)‐polarized immune response. Susceptible mouse strains, in contrast, mount an inappropriate Th1 response to T. muris infection. Expression of the chemokine CXCL13 by stromal follicular dendritic cells attracts CXCR5‐expressing cells towards the B‐cell follicles. Previous studies using a complex in vivo depletion model have suggested that CXCR5‐expressing conventional dendritic cells (cDC) help regulate the induction of Th2‐polarized responses. Here, transgenic mice with CXCR5 deficiency specifically restricted to CD11c⁺ cells were used to determine whether the specific absence CXCR5 on CD11c⁺ cells such as cDC would influence susceptibility to oral T. muris infection by affecting the Th1/Th2 balance. We show that in contrast to control mice, those which lacked CXCR5 expression on CD11c⁺ cells failed to clear T. muris infection and developed cytokine and antibody responses that suggested a disturbed Th1/Th2 balance with enhanced IFN‐γ expression. These data suggest an important role of CXCR5‐expressing CD11c⁺ cells such as cDC in immunity to oral T. muris infection.     

Combination of HIV-1-specific CD4 Th1 cell responses and IgG2 antibodies is the best predictor for persistence of long-term nonprogression

BACKGROUND: Strong T cell and antibody responses to human immunodeficiency virus (HIV), low virus production, and some genetic traits have been individually associated with nonprogression of HIV infection, but the best correlate with protection against disease progression remains unknown. METHODS: We prospectively followed 66 untreated long-term nonprogressors and analyzed relationships between HIV-1-specific CD4 T helper (Th) 1 and CD8 T cell responses and HIV-1-specific antibodies, HIV-1 RNA and proviral DNA loads, host genes, and CD4 Th1 cell counts at entry into the study and 4 years later. RESULTS: HIV-1 p24-specific CD4 Th1 cell proliferation, interferon (IFN)- gamma production, and IFN- gamma -producing cell frequencies at entry significantly and negatively correlated with HIV-1 RNA and proviral DNA loads and were independent of CD4 Th1 cell counts and host genes. HIV-1 Gag-specific IFN- gamma -producing CD8 T cell frequencies correlated with HIV-1 proviral DNA loads but not with RNA loads. Only high frequencies of HIV-1 p24-specific CD4 Th1 cells combined with HIV-1 gp41-specific IgG2 antibodies significantly predicted persistence of high CD4 Th1 cell counts. CONCLUSION: HIV-1-specific CD4 Th1 responses combined with IgG2 antibodies and IFN- gamma -producing CD4 Th1 cells are better predictors of long-term nonprogression than are virus parameters, host genes, or HIV-1-specific CD4 Th1 or CD8 T cell proliferation.     

Changes in bone marrow and peripheral blood lymphocyte subset findings with onset of hepatitis-associated aplastic anemia

Rationale:Hepatitis-associated aplastic anemia (HAAA) is a rare illness that results in bone marrow failure following hepatitis development. The etiological agent remains unknown in most HAAA cases. However, clinical features of the disease and immunotherapy response indicate that immune-mediated factors play a central role in the pathogenesis of HAAA. Activation of cytotoxic T cells and increase in CD8 cells could exert cytotoxic effects on the myelopoietic cells in the bone marrow.Patient concerns:A 15-month-old boy was brought to our hospital with complaints of generalized petechiae and purpura observed a week prior to hospitalization. His liver was palpated 3 cm below the costal margin, platelet count was 0 × 10⁴/μL, and alanine aminotransferase level was 1346 IU/L. A blood test indicated cytomegalovirus infection, and 3 bone marrow examinations revealed progressive HAAA. As the disease progressed to the 3^rd, 6^th, and 9^th week after onset, CD4⁺ T cells were markedly decreased, CD8⁺ T cells were markedly increased, and the CD4/CD8 ratio was significantly decreased. The number of B cells and natural killer cells decreased with time, eventually reaching 0.0%.Diagnosis:HAAA.Interventions:Rabbit antithymocyte globulin and eltrombopag olamine (a thrombopoietin receptor agonist) were administered.Outcomes:The patient''s platelet count returned to normal, and bone marrow transplantation was avoided. The peripheral blood lymphocytes (PBLs) improved as the patient''s general condition recovered.Lessons:This case demonstrates that HAAA induced by cytomegalovirus infection features decreasing CD4⁺ and increasing CD8⁺ PBLs as the bone marrow hypoplasia progresses. The PBLs return to their normal levels with the recovery from the disease. Our case findings thus support the involvement of immunological abnormality in HAAA.     

Robust and Persistent B- and T-Cell Responses after COVID-19 in Immunocompetent and Solid Organ Transplant Recipient Patients

The development and persistence of SARS-CoV-2-specific immune response in immunocompetent (IC) and immunocompromised patients is crucial for long-term protection. Immune response to SARS-CoV-2 infection was analysed in 57 IC and 15 solid organ transplanted (TX) patients. Antibody responses were determined by ELISA and neutralization assay. T-cell response was determined by stimulation with peptide pools of the Spike, Envelope, Membrane, and Nucleocapsid proteins with a 20-h Activation Induced Marker (AIM) and 7-day lymphoproliferative assays. Antibody response was detected at similar levels in IC and TX patients. Anti-Spike IgG, IgA and neutralizing antibodies persisted for at least one year, while anti-Nucleocapsid IgG declined earlier. Patients with pneumonia developed higher antibody levels than patients with mild symptoms. Similarly, both rapid and proliferative T-cell responses were detected within the first two months after infection at comparable levels in IC and TX patients, and were higher in patients with pneumonia. T-cell response persisted for at least one year in both IC and TX patients. Spike, Membrane, and Nucleocapsid proteins elicited the major CD4⁺ and CD8⁺ T-cell responses, whereas the T-cell response to Envelope protein was negligible. After SARS-CoV-2 infection, antibody and T-cell responses develop rapidly and persist over time in both immunocompetent and transplanted patients.     

Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses

One half of a group of 20 patients with human papillomavirus type 16 (HPV16)-induced vulvar intraepithelial neoplasia grade 3 displayed a complete regression (CR) after therapeutic vaccination with HPV16 E6/E7 synthetic long peptides. Patients with relatively larger lesions generally did not display a CR. To investigate immune correlates of treatment failure, patients were grouped according to median lesion size at study entry, and HPV16-specific immunity was analyzed at different time points by complementary immunological assays. The group of patients with smaller lesions displayed stronger and broader vaccine-prompted HPV16-specific proliferative responses with higher IFNγ (P = 0.0003) and IL-5 (P < 0.0001) levels than patients with large lesions. Characteristically, this response was accompanied by a distinct peak in cytokine levels after the first vaccination. In contrast, the patient group with larger lesions mounted higher frequencies of HPV16-specific CD4⁺CD25⁺Foxp3⁺ T cells (P = 0.005) and displayed a lower HPV16-specific IFNγ/IL-10 ratio after vaccination (P < 0.01). No disparity in T memory immunity to control antigens was found, indicating that the differences in HPV-specific immunity did not reflect general immune failure. We observed a strong correlation between a defined set of vaccine-prompted specific immune responses and the clinical efficacy of therapeutic vaccination. Notably, a high ratio of HPV16-specific vaccine-prompted effector T cells to HPV16-specific CD4⁺CD25⁺Foxp3⁺ T cells was predictive of clinical success. Foxp3⁺ T cells have been associated previously with impaired immunity in malignancies. Here we demonstrate that the vaccine-prompted level of this population is associated with early treatment failure.     

Cytotoxic cell involvement in human cutaneous leishmaniasis: assessments in active disease,under therapy and after clinical cure

Cutaneous leishmaniasis (CL) is an important public health issue worldwide. The control of Leishmania infection depends on cellular immune mechanisms, and the inflammatory response may contribute to pathogenesis. A beneficial role of CD8⁺ T lymphocytes has been proposed; nevertheless, other studies suggest a cytotoxic role of CD8⁺ T lymphocytes involved in tissue damage, showing controversial role of these cells. The goal of the current study was to understand the immunopathology of CL and determine the profile of cytotoxic cells – such as CD4⁺ T, natural killer and natural killer T cells – that might be involved in triggering immunological mechanisms, and may lead to cure or disease progression. The frequencies of cytotoxic cell populations in peripheral blood, obtained from patients with active disease, during treatment and after clinical healing, were assessed by flow cytometry. Cytotoxicity could not be related to a deleterious role in Leishmania braziliensis infection, as patients with active CL showed similar percentages of degranulation to healthy individuals (HI). Cured patients exhibited a lower percentage of degranulating cells, which may be due to a downregulation of the immune response. The understanding of the immunopathological mechanisms involved in CL and the commitment of cytotoxic cells enables improvements in therapeutic strategies.     

Deficit of circulating CD19+CD24hiCD38hi regulatory B cells in severe aplastic anaemia

Immune aplastic anaemia (AA) is caused by cytotoxic T lymphocytes (CTLs) that destroy haematopoietic stem and progenitor cells. Enhanced type 1 T helper (Th1) responses and reduced regulatory T cells (Tregs) are involved in the immune pathophysiology. CD24^hiCD38^hi regulatory B cells (Bregs) suppress CTLs and Th1 responses, and induce Tregs via interleukin 10 (IL-10). We investigated circulating B-cell subpopulations, including CD24^hiCD38^hi Bregs, as well as total B cells, CD4⁺ T cells, CD8⁺ T cells and natural killer cells in 104 untreated patients with severe and very severe AA, aged ≥18 years. All patients were treated with standard immunosuppressive therapy (IST) plus eltrombopag. CD24^hiCD38^hi Bregs were markedly reduced in patients with AA compared to healthy individuals, especially in very severe AA, but residual Bregs remained functional, capable of producing IL-10; total B-cell counts and the other B-cell subpopulations were similar to those of healthy individuals. CD24^hiCD38^hi Bregs did not correlate with responses to IST, and they recovered to levels present in healthy individuals after therapy. Mature naïve B-cell counts were unexpectedly associated with IST response. Markedly reduced CD24^hiCD38^hi Bregs, especially in very severe AA, with recovery after IST suggest Breg deficits may contribute to the pathophysiology of immune AA.     

Human immunodeficiency virus type I-specific CD8<Superscript>+</Superscript>T cell subset abnormalities in chronic infection persist through effective antiretroviral therapy

Background  

Effective highly active antiretroviral therapy (HAART) reduces human immunodeficiency virus (HIV) replication, restores CD4⁺ T lymphocyte counts and greatly reduces the incidence of opportunistic infections. While this demonstrates improved generalized immune function, rapid rebound to pre-treatment viral replication levels following treatment interruption indicates little improvement in immune control of HIV replication. The extent to which HAART can normalize HIV-specific CD8⁺ T cell function over time in individuals with chronic infection remains an important unresolved issue. In this study, we evaluated the magnitude, general specificity and character of HIV specific CD8⁺ T cell responses at four time points across 2-9 years in 2 groups of chronically infected individuals separated on the basis of either effective antiretroviral suppression or ongoing replication of HIV.