Costimulation through OX40 is crucial for induction of an alloreactive human T-cell response

The alloreactive immune response is a series of events initiated by the interaction of T cells with allogeneic dendritic cells (DCs), involving alloantigen recognition and costimulatory signals. In this study, we investigated the role of OX40 in alloreactivity in vitro. We first demonstrated that anti-OX40 ligand (anti-OX40L) monoclonal antibody (mAb) could markedly suppress the mixed leucocyte reaction (MLR) of peripheral blood mononuclear cells (PBMC). To further define the contribution of the OX40/OX40L system to the MLR, we set up a co-culture system of CD4+ T cells and allogeneic monocyte-derived dendritic cells (DCs). After 2 days, OX40 expression was induced on CD4+ T cells and this induction was strongly inhibited by the addition of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-Fc fusion protein, suggesting that the expression of OX40 during alloreaction is dependent on CD28 signalling. Next we examined the effects of anti-OX40L mAb, CTLA-4-Fc fusion protein and anti-human leucocyte antigen (HLA)-DR mAb on the proliferative response of CD4+ T cells to allogeneic DCs. The proliferation of T cells was almost completely suppressed by anti-OX40L mAb, which was comparable with that of CTLA-4-Fc. Measurement of interleukin-2 (IL-2) production in the culture supernatants showed that suppression of a proliferative response was at least in part ascribed to reduced IL-2 production. Furthermore, purified OX40L- allogeneic DCs could induce considerable proliferation of CD4+ T cells, which was suppressed by anti-OX40L mAb. These results suggest that the OX40/OX40L system is crucial for induction of the allogeneic T-cell response and the OX40/OX40L system is subsequent to and dependent on CD28 signalling, but is crucial for the end outcome of the human alloreactive T-cell response.     

Early reduction of the over-expression of CD40L, OX40 and Fas on T cells in HIV-1 infection during triple anti-retroviral therapy: possible implications for lymphocyte traffic and functional recovery.

Fas, CD40L and OX40 are members of the tumour necrosis factor (TNF) receptor superfamily with critical roles in T cell activation and death, B cell function, dendritic cell maturation and leucocyte traffic regulation. The aim of this study was to evaluate the effects of anti-retroviral therapy (HAART) on CD40L, OX40 and Fas expression on freshly isolated peripheral blood T cells by three-colour flow cytometry and compare them with lymphoproliferative responses, peripheral blood cell counts and viral load. Fourteen asymptomatic HIV-1+ patients treated with Lamivudine, Stavudine and Nelfinavir were prospectively investigated sequentially for 48 weeks. At baseline, patients exhibited significantly enhanced proportions and counts of CD40L+ and OX40+ cells within the CD4 subset which were corrected by weeks 8-16 of HAART. Interestingly, in the five patients showing viral load rebound during therapy in spite of increasing CD4 counts, the reduction of the levels of these costimulatory molecules was similarly maintained. Therapy induced a decrease in the over-expression of Fas, particularly in the CD4 subset where normal levels were reached at week 8. This reduction occurred in parallel with the major recovery of lymphoproliferative responses. Higher basal levels and lower reduction of Fas were associated with suboptimal suppression of viraemia. In conclusion, this previously undescribed increased expression of CD40L and OX40 may play a role in the HIV-associated pan-immune activation and represent a possible target for immunointervention, as suggested for several immunologically mediated diseases. Moreover, HAART induced an early correction of the over-expression of Fas, CD40L and OX40 in CD4 T cells which could be involved in the recovery of the cell traffic disturbances and in the T cell renewal capacity.     

OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice

Interactions between APC and T lymphocytes have been implicated as a major factor contributing to inflammatory bowel disease. To test whether OX40/OX40L interaction plays a role in chronic intestinal inflammation, we induced chronic colitis using dextran sulfate sodium and treated the mice with a murine fusion protein (OX40-IgG). Treatment resulted in a dose-dependent and significant reduction of intestinal inflammation (46%) as measured by a histologic score. IL-10 and IL-5 production from mesenteric lymph node cells increased 20-fold and 18-fold, respectively. In colonic tissue, IL-10 mRNA levels increased and the expression of T-bet was decreased to 30%. IL-10 neutralization partly inhibited the beneficial effects of OX40-IgG treatment. Surprisingly, despite the reduction of inflammation we found the number and size of colonic lymphoid follicles increased, with an accumulation of CD4(+) cells in the mantle area. In contrast, the number of CD4(+) cells infiltrating the mucosa was significantly reduced, as was their CXCR5 expression (24-fold). We conclude that OX40/OX40L interaction contributes to the perpetuation of chronic colitis partly by suppressing IL-10 production. Furthermore, our data suggest that the OX40/OX40L-induced CXCR5 expression on CD4(+) cells may be important for the inflammatory process by allowing migration to the germinal center for further differentiation of CD4(+) cells before they infiltrate the chronically inflamed mucosa.     

Expression of tumour necrosis factor (TNF) ligand superfamily co-stimulatory molecules CD30L, CD27L, OX40L, and 4-1BBL in murine hearts with acute myocarditis caused by Coxsackievirus B3.

Antigen-specific T-cells infiltrate the heart and play an important role in the myocardial damage involved in acute myocarditis and dilated cardiomyopathy. To investigate the roles of the co-stimulatory molecules CD30/CD30L, CD27/CD27L, OX40/OX40L, and 4-1BB/4-1BBL, which belong to the tumor necrosis factor (TNF) receptor/ligand superfamily, in the development of acute viral myocarditis, the expression of these molecules was first analysed in the hearts of mice with acute myocarditis induced by Coxsackievirus B3 (CVB3) in vivo. Secondly, the induction of these molecules was evaluated on cultured cardiac myocytes treated with interferon (IFN)-gamma and the interleukin (IL)-6 production by cultured cardiac myocytes was analysed by stimulation with monoclonal antibodies (MAbs) against these molecules in vitro. Thirdly, the effects of in vivo administration of anti-CD30L, anti-CD27L, anti-OX40L, or anti-4-1BBL MAb on the development of acute viral myocarditis were examined. CVB3-induced myocarditis resulted in the induction of CD30L and 4-1BBL on the surface of cardiac myocytes, confirmed by treatment with IFN-gamma in vitro. CD27L and OX40L were constitutively expressed on cardiac myocytes in vivo and in vitro. Anti-CD30L and anti-4-1BBL MAbs stimulated IL-6 production by cardiac myocytes in vitro. Furthermore, in vivo anti-4-1BBL MAb treatment significantly decreased the myocardial inflammation, whereas the other MAbs did not. These findings suggest that TNF ligand superfamily co-stimulatory molecules, especially 4-1BBL, play an important role in the development of acute viral myocarditis and raise the possibility that immunotherapy with anti-4-1BBL MAb may be of benefit in acute viral myocarditis.     

Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus

T helper 1 driven immune responses facilitate host defence during viral infections. Because interleukin-18 (IL-18) mediates T helper 1 driven immune responses, and since mature IL-18 is up-regulated in human macrophages after influenza virus infection in vitro, it has been suggested that IL-18 plays an important role in the immune response to influenza. To determine the role of IL-18 in respiratory tract infection with influenza, IL-18 gene-deficient (IL-18(-/-)) and normal wildtype mice were intranasally inoculated with influenza A virus. Influenza resulted in an increase in constitutively expressed IL-18 in the lungs of wildtype mice. The clearance of influenza A was inhibited by IL-18, as indicated by reduced viral loads on day 8 and day 12 after infection in IL-18(-/-) mice. This enhanced viral clearance correlated with increased CD4(+) T-cell activation in the lungs as reflected by CD69 expression on the cell surface. Surprisingly, interferon-gamma (IFN-gamma) levels were similar in the lungs of IL-18(-/-) mice and wildtype mice. Intracellular IFN-gamma staining revealed similar expression levels in lung-derived natural killer cells, CD4(+) and CD8(+) T cells, indicating that IFN-gamma production is IL-18-independent during influenza virus infection. Tumour necrosis factor-alpha production by CD4(+) T cells was significantly lower in IL-18(-/-) mice than in wildtype mice. Our data indicate that endogenous IL-18 impairs viral clearance during influenza A infection.     

Thymic volume predicts CD4 T-cell decline in HIV-infected adults under prolonged treatment interruption

OBJECTIVE: To analyze the predictive capacity of thymic volume in CD4 T-cell loss after treatment interruption in HIV-infected patients with high nadir CD4 count. METHODS: Thirty-nine HIV-infected patients with CD4 counts greater than or equal to 500 cells/microL, nadir CD4 counts greater than or equal to 250 cells/microL, and plasma viral loads less than 50 copies/mL for at least the past 12 months began a treatment interruption program. The event of interest for this study was the decrease of CD4 count below 350 cells/microL. Kaplan-Meier curves were used for all time-to-event analyses, and log-rank tests were used for comparison between groups in the univariate analysis. All variables with statistical association with CD4 T-cell loss were analyzed using multivariate Cox proportional hazards regression models. RESULTS: Twenty-three percent of the patients had a decrease in CD4 count to less than 350 cells/microL. In the univariate analysis, only thymic volume was statistically significant with this event (P = 0.02). Nadir CD4 count nearly reached statistical significance. However, age, sex, HCV coinfection, CD4 count, T-cell receptor excision circle-bearing cells, and early viral load rebound did not show statistical differences. Thymic volume and CD4 T-cell loss were independently associated using Cox proportional hazards regression model (P = 0.04; relative risk, 0.76; 95% confidence interval, 0.59-0.99). CONCLUSIONS: In this study, we demonstrate for the first time that thymic volume predicts CD4 T-cell loss in patients with nadir CD4 count greater than or equal to 250 cells/muL under treatment interruption.     

Robust interferon-α and IL-12 responses by dendritic cells are related to efficient CD4+ T-cell recovery in HIV patients on ART

Amongst HIV patients with successful virological responses to antiretroviral therapy (ART), poor CD4(+) T-cell recovery is associated with low nadir CD4(+) T-cell counts and persistent immune activation. These factors might be influenced by dendritic cell (DC) function. Interferon-α-producing plasmacytoid DC and IL-12-producing myeloid DC were quantified by flow cytometry after stimulation with agonists to TLR7/8 (CL075) or TLR9 (CpG-ODN). These were compared between patients who achieved CD4(+) T-cell counts above or below 200 cells/μL after 6 months on ART (High vs. Low groups). High Group patients had more DC producing interferon-α or IL-12 at Weeks 6 and 12 on ART than Low Group patients. The frequencies of cytokine-producing DC at Week 12 were directly correlated with CD4(+) T-cell counts at baseline and at Week 12. Patients with good recovery of CD4(+) T-cells had robust TLR-mediated interferon-α responses by plasmacytoid DC and IL-12 responses by myeloid DC during early ART (1-3 months).     

A Randomized Trial of Nelfinavir,Ritonavir, or Delavirdine in Combination with Saquinavir-SGC and Stavudine in Treatment-Experienced HIV-1-Infected Patients

Abstract

Purpose: To evaluate the 24-week impact of saquinavir-enhancing antiretroviral therapy on viral replication in patients previously treated with nucleoside analogues with or without prior saquinavir hard-gel capsules (HGC). Method: Patients were randomized in three groups to receive the following: Group 1—nelfinavir (750 mg tid), saquinavir soft-gel capsule (SGC) (800 mg tid), and stavudine (40 mg bid); Group II—ritonavir (400 mg bid), saquinavir-SGC (400 mg bid), and stavudine (40 mg bid); or Group III—delavirdine (400 mg tid), saquinavir-SGC (800 mg tid), and stavudine (40 mg bid). Viral loads, CD4 count, and safety were assessed over a 24-week period with an additional 6-month follow-up. Results: 73 patients received randomized therapy; 14 of whom were SQV naïve, with a median baseline viral load of 3.6 log₁₀ and a CD4 count of 370 cells/mm³. By 6 months, the median decreases in plasma viral loads were 0.26, 0.71, and 0.29 log₁₀ copies/mL for groups I, II, and III, respectively. The median increases in CD4 counts, for groups I, II, and III, were 52, 40, and 69 cells/mm³ at 6 months, respectively. Changes in viral load and CD4 counts at 6 months and 1 year were not significantly different between the treatment groups. More patients discontinued therapy in the ritonavir arm (35%) for drug intolerance or toxicity compared to either the nelfinavir or delavirdine arms (15% and 5%, respectively). In a multivariate analysis, baseline viral load, younger age, and baseline saquinavir resistance were significantly associated with detectable viral load at 24 weeks. Conclusion: The use of antiretroviral agents that pharmacokinetically boost saquinavir levels has a modest benefit in saquinavir-experienced patients.     

Activated B cells modified by electroporation of multiple mRNAs encoding immune stimulatory molecules are comparable to mature dendritic cells in inducing in vitro antigen-specific T-cell responses

Ex-vivo-activated B cells are an alternative source of antigen-presenting cells (APCs) and a potential replacement for dendritic cells (DCs) in immunotherapy. However, the ability of ex-vivo-activated B cells to function as potent APCs has been a concern, especially when compared to DCs. Our study investigated whether modification of activated B cells with immune stimulatory molecules could enhance the ability of activated B cells to stimulate T cells. We show that murine splenic B cells, activated with a combination of Toll-like receptor agonist and agonistic anti-CD40, stimulated antigen-specific CD8+ T cells more efficiently than cells activated with Toll-like receptor agonist or anti-CD40 alone, probably by down-regulation of the immune regulatory cytokine interleukin-10 (IL-10). However, the activated B cells were still poor T-cell stimulators compared to mature DCs. Therefore, we modified the activated B cells by simultaneous electroporation of multiple messenger RNAs encoding costimulatory molecules (OX40L and 4-1BBL), cytokines (IL-12p35 and IL-12p40) and antigen. We found that de novo expression or overexpression of OX40L, 4-1BBL and IL-12p70 on activated B cells synergistically enhanced proliferation as well as IL-2 and interferon-gamma production by CD8+ T cells. Furthermore, the RNA-modified activated B cells induced antigen-specific cytotoxic T lymphocyte responses as efficiently as mature DCs in vitro. Unexpectedly, modified activated B cells were inferior to mature DCs at in vivo induction of CD8+ T-cell responses. In summary, activated B cells modified to express immune stimulatory molecules are a potent alternative to DCs in immunotherapy.     

OX40-Mediated cosignal enhances the maturation of naive human CD4+ T cells into high IL-4-producing effectors

Our previous studies have indicated that naive human CD4+ T cells of neonatal or adult origin may be the initial source of IL-4 which is required for their development into Th2 effectors. In addition to minute amounts of IL-4, anti-CD3/B7.1-activated naive cells also release readily detectable levels of IL-13 and IFN-gamma. The production of IL-4 and IL-13 by naive T cells is differentially regulated by TGF-beta and IL-12. Shortly after activation, naive T cells express surface OX40, a TNF-R family member whose ligand (OX40L) is constitutively expressed on a subset of dendritic cells. Engagement of OX40 on activated naive T cells increases their expression of IL-4 and IL-13, suppresses that of IFN-gamma and promotes their development into Th2-like effectors.     

The CD40/CD40 ligand interaction is required for resistance to toxoplasmic encephalitis

Since the CD40/CD40 ligand (CD40L) interaction is involved in the regulation of macrophage production of interleukin 12 (IL-12) and T-cell production of gamma interferon (IFN-gamma), effector cell functions associated with resistance to Toxoplasma gondii, the role of CD40L in immunity to this parasite was assessed. Infection of C57BL/6 mice with T. gondii results in an upregulation of CD40 expression on accessory cell populations at local sites of infection as well as in lymphoid tissues. Splenocytes from C57BL/6 mice infected with T. gondii for 5 days produced high levels of IL-12 and IFN-gamma when stimulated with toxoplasma lysate antigen, and blocking CD40L did not significantly alter the production of IFN-gamma or IL-12 by these cells. Similar results were observed with splenocytes and mononuclear cells isolated from the brains of chronically infected mice. Interestingly, although CD40L(-/-) mice infected with T. gondii produced less IL-12 than wild-type mice, they produced comparable levels of IFN-gamma but succumbed to toxoplasmic encephalitis 4 to 5 weeks after infection. The inability of CD40L(-/-) mice to control parasite replication in the brain correlated with the ability of soluble CD40L, in combination with IFN-gamma, to activate macrophages in vitro to control replication of T. gondii. Together, these results identify an important role for the CD40/CD40L interaction in resistance to T. gondii. However, this interaction may be more important in the control of parasite replication in the brain rather than the generation of protective T-cell responses during toxoplasmosis.     

Expression of tumour necrosis factor (TNF) receptor/ligand superfamily co-stimulatory molecules CD40, CD30L,CD27L,and OX40L in murine hearts with chronic ongoing myocarditis caused by Coxsackie virus B3

T-cell-mediated myocardial damage has been shown to be involved in acute myocarditis and dilated cardiomyopathy. It is necessary for T-cells to receive a co-stimulatory signal as well as the main signal through the T-cell receptor for antigen-specific T-cell activation to occur. To investigate the roles of the co-stimulatory molecules CD40/CD40L, CD30/CD30L, CD27/CD27L, and OX40/OX40L, which belong to the tumour necrosis factor (TNF) receptor/ligand superfamily, in the development of chronic ongoing myocarditis, the expression of CD40, CD30L, CD27L, and OX40L was analysed in the hearts of A/J mice with myocarditis induced by Coxsackie virus B3 (CVB3). The expression of CD40L, CD30, CD27, and OX40 was also examined on the infiltrating cells. Furthermore, the induction of CD40, CD30L, CD27L, and OX40L was evaluated on cultured cardiac myocytes treated with interferon (IFN)-γ. CVB3-induced myocarditis resulted in the induction of CD40 and CD30L on the surface of cardiac myocytes. Induction of CD40 and CD30L on cardiac myocytes was confirmed by treatment with IFN-γ in vitro. CD27L and OX40L were expressed on cardiac myocytes in vivo and in vitro. The expression of CD27L and OX40L on cardiac myocytes was increased, at least partly, by CVB3-induced myocarditis in vivo. Many infiltrating cells expressed CD27 and OX40, whereas much smaller numbers expressed CD40L and CD30. The induction of these molecules, especially CD40 and CD30L, on cardiac myocytes strongly suggests that cardiac myocytes may co-stimulate T-cells and induce cytokine production by T-cells and humoral immune responses. This may play an important role in the pathogenesis of the resulting myocardial damage. Copyright © 1999 John Wiley & Sons, Ltd.     

Levels of soluble CD40 ligand (CD154) in serum are increased in human immunodeficiency virus type 1-infected patients and correlate with CD4(+) T-cell counts

CD40 ligand (CD40L or CD154) is a costimulatory molecule expressed mainly on activated CD4(+) T cells. Concentrations of the soluble form of CD40L (sCD40L) in serum were determined for a cohort of 77 human immunodeficiency virus type 1 (HIV-1)-infected patients before and after initiation of highly active antiretroviral treatment (HAART) by a quantitative enzyme-linked immunosorbent assay. Circulating sCD40L levels were higher by twofold in untreated patients than in healthy controls (means +/- standard deviations [SD]: 1.41 +/- 1.48 versus 0.69 +/- 0.59 ng/ml; P < 0.001). HIV-1-infected patients classified as CD4 T-cell category 1 had significantly higher sCD40L levels than patients classified as CD4 categories 2 and 3 (mean +/- SD: 2.08 +/- 1.46 ng/ml versus 1.57 +/- 1.58 [category 2] and 0.94 +/- 1.25 ng/ml [category 3]; P = 0.046), while no correlation with clinical categories A, B, and C was found. Individual serum sCD40L levels correlated with CD4(+) T-cell counts (P = 0.039) but not with viral load, gamma globulin levels, or acute-inflammatory-response markers. After 8 to 12 months of HAART, a further threefold increase of serum sCD40L levels, which paralleled the increase of CD4(+) T-cell counts, was observed. These novel findings suggest that sCD40L measurement in HIV-1-infected patients could serve as a new surrogate marker useful in the assessment of treatment efficacy, especially in settings where well-equipped laboratories and funding required for CD4(+) T-cell count and viral load measurements are not available.     

Distinct cytokine regulation by cholera toxin and type II heat-labile toxins involves differential regulation of CD40 ligand on CD4(+) T cells

Cholera toxin (CT) and the type II heat-labile enterotoxins (HLT) LT-IIa and LT-IIb act as potent systemic and mucosal adjuvants and induce distinct T-helper (Th)-cell cytokine profiles. In the present study, CT and the type II HLT were found to differentially affect cytokine production by anti-CD3-stimulated human peripheral blood mononuclear cells (PBMC), and the cellular mechanisms responsible were investigated. CT suppressed interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha), and IL-12 production by PBMC cultures more than either LT-IIa or LT-IIb. CT but not LT-IIa or LT-IIb reduced the expression of CD4(+) T-cell surface activation markers (CD25 and CD69) and subsequent proliferative responses of anti-CD3-stimulated T cells. CT but not LT-IIa or LT-IIb significantly reduced the expression of CD40 ligand (CD40L) on CD4(+) T cells. In a coculture system, CT-treated CD4(+) T cells induced significantly less TNF-alpha and IL-12 p70 production by both autologous monocytes and monocyte-derived dendritic cells than either LT-IIa- or LT-IIb-treated CD4(+) T cells. These findings demonstrate that CT, LT-IIa, and LT-IIb differentially affect CD40-CD40L interactions between antigen-presenting cells and T cells and help explain the distinct cytokine profiles observed with type I and type II HLT when used as mucosal adjuvants.     

A randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, and 5-day cycles of intravenous recombinant human interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100-300 CD4+ T cells

The effect of length of therapy on the safety and efficacy profile of continuous intravenous (CIV) interleukin-2 (IL-2) in combination with antiretroviral therapy (ART) was evaluated in 81 HIV-seropositive patients with CD4(+) T-cell counts of 100-300/mm(3). Patients were randomized to CIV IL-2 (12 mIU/day) for 3, 4, or 5 days plus ART every 8 weeks for six cycles, or to ART alone. The mean percent increase in CD4(+) T-cell counts was 24.5% for IL-2 recipients compared with a mean percent decrease of 30.5% for control patients (P = 0.005). Increasing duration of CIV IL-2 therapy resulted in improved CD4(+) T-cell response. The most frequent clinical adverse events and laboratory abnormalities were predominantly of grade 1 or 2 severity. However, grade 3 or 4 events were reported in 57%, 60%, and 84% of the 3-, 4-, and 5-day CIV IL-2 patients, respectively. Serious adverse events, mainly due to the requirement of hospitalization, occurred in 20% of IL-2 recipients, compared with 10% of control patients. Viral load during the course of the study was not different among the treatment groups. IL-2 therapy in cycles of 5 days resulted in an optimal increase in CD4(+) T-cell counts and is the preferred cycle length for IL-2 therapy geared toward increasing CD4(+) T-cell numbers.     

Decreased CD40 ligand induction in CD4 T cells and dysregulated IL-12 production during HIV infection.

During HIV infection various cytokines are overproduced in early stages, whereas in advanced disease cytokines of the T helper 1 type (e.g. interferon-gamma (IFN-gamma)) are selectively deficient. During antigenic stimulation, the production of type-1 cytokines is enhanced by IL-12, secreted by antigen-presenting cells (APC) after their interaction with activated CD4 T cells. Two factors are essential in this process: priming APC with IFN-gamma and triggering the CD40 receptor on APC by CD40 ligand (CD40L). In view of the importance of this pathway, we compared its regulation in HIV-infected and control subjects. After cross-linking of the T cell receptor (TCR)/CD3 complex, the proportional expression of CD40L was similar on CD4+ T cells from controls and from patients with high circulating CD4 T counts (> 500/microl), but CD40L up-regulation was significantly reduced in patients with more advanced disease. Simultaneous triggering of the costimulatory receptor CD28 on T cells through its natural ligand CD80 partly corrected the CD40L defect in patients with intermediate CD4 T counts (200-500), but not in AIDS patients. Early production of IFN-gamma was preserved in lymphocytes from HIV+ patients. The expression of CD40 on peripheral monocytes from HIV+ subjects was increased in a disease stage-related fashion. Stimulation of mononuclear cells through cell-bound CD40L and soluble IFN-gamma induced significantly higher IL-12 in cultures from patients with > 200 circulating CD4 T cells, whereas IL-12 production was marginally decreased in cultures from patients with < 200 CD4 T cells, compared with healthy control cultures. In conclusion, our data suggest that impaired CD40L induction on CD4 T cells contributes to deficient type-1 responses through decreased IL-12 production in AIDS infection, whereas enhanced CD40-mediated IL-12 production in less advanced stages might contribute to increased levels of various cytokines in early disease     

Primary HIV-1 subtype C infection in Ethiopia

Between 1997 and 2001, 1624 Ethiopian factory workers were enrolled in prospective HIV-1 cohorts in Ethiopia, at Akaki and Wonji towns. HIV-1 seroprevalence at intake was 11.8% (Akaki) and 7.1% (Wonji). HIV-1 incidence was .75 per 100 person-years (Akaki) and .35 per 100 person-years (Wonji). During follow up, CD4 T-cell counts remained significantly lower and CD8 T-cell counts significantly higher in Ethiopian seroconverters compared with Dutch seroconverters. Viral loads were lower in Ethiopian seroconverters versus Dutch seroconverters in the first months after seroconversion, subsequently increasing to similar levels. All 20 Ethiopian seroconverters were infected with HIV-1 subtype C (15 with sub-cluster C' and 5 with sub-cluster C). Viral loads were higher in sub-cluster C'-infected Ethiopian seroconverters. One subject demonstrated a window period of at least 204 days, combined with a high preseroconversion viral load and no decline of CD4 T cells over a follow-up period of at least 3 years.     

CD117⁺ CD3⁻ CD56⁻ OX40Lhigh cells express IL-22 and display an LTi phenotype in human secondary lymphoid tissues

Here, we identify cells within human adult secondary lymphoid tissues that are comparable in phenotype and location to the lymphoid tissue inducer (LTi) cells that persist in the adult mouse. Identified as CD117(+) CD3(-) CD56(-) cells, like murine LTi cells, they lack expression of many common lineage markers and express CD127, OX40L and TRANCE. These cells were detected at the interface between the B- and T- zones, as well as at the subcapsular sinus in LNs, the location where LTi cells reside in murine spleen and LNs. Furthermore, like murine LTi cells, these cells expressed high levels of IL-22 and upregulated IL-22 expression upon IL-23 stimulation. Importantly, these cells were not an NK cell subset since they showed no expression of IFN-γ and perforin. Interestingly, a subset of the CD117(+) CD3(-) CD56(-) OX40L(+) population expressed NKp46, again similar to recent findings in mice. Finally, these cells supported memory CD4(+) T-cell survival in an OX40L-dependent manner. Combined, these data indicate that the CD117(+) CD3(-) CD56(-) OX40L(+) cells in human secondary lymphoid tissues are comparable in phenotype, location and function to the LTi cells that persist within adult murine secondary lymphoid tissues.