Recurrent infection transiently expands human tissue T cells while maintaining long-term homeostasis.

Chronic viral infections are known to lead to T cell exhaustion or dysfunction. However, it remains unclear if antigen exposure episodes from periodic viral reactivation, such as herpes simplex virus type-2 (HSV-2) recrudescence, are sufficient to induce T cell dysfunction, particularly in the context of a tissue-specific localized, rather than a systemic, infection. We designed and implemented a stringent clinical surveillance protocol to longitudinally track both viral shedding and in situ tissue immune responses in a cohort of HSV+ volunteers that agreed to avoid using anti-viral therapy for the course of this study. Comparing lesion to control skin biopsies, we found that tissue T cells expanded immediately after reactivation, and then returned numerically and phenotypically to steady state. T cell responses appeared to be driven at least in part by migration of circulating T cells to the infected tissue. Our data indicate that tissue T cells are stably maintained in response to HSV reactivation, resembling a series of acute recall responses.

Mucosal tissue regulatory T cells are integral in balancing immunity and tolerance at portals of antigen entry.

Foxp3+ regulatory T cells (Tregs) are a subset of CD4+ T cells that exert suppressive control over other immune cells. Tregs are critical for preventing systemic autoimmunity and maintaining peripheral tolerance, and yet they also assist in orchestration of immunity to pathogenic insult, wherein they limit collateral immunopathology and assist in facilitating a fine balance between immune tolerance and effector activity. Tregs have been extensively studied in lymphoid tissues, and a growing body of work has characterized phenotypically distinct Tregs localized in various nonlymphoid tissue compartments. These tissue Tregs can perform location-specific, alternative functions, highlighting their dynamic, context-dependent roles. Tregs have also been identified in mucosal tissues where specialized physiological functions are paramount, including helping the host to respond appropriately to pathogenic versus innocuous antigens that are abundant at mucosal portals of antigen entry. As in other tissue Treg compartments, mucosal Tregs in the respiratory, gastrointestinal, and genitourinary tracts are distinct from circulating counterparts and can carry out mucosa-specific functions as well as classic suppressive functions that are the hallmark of Tregs. In this review, we summarize current knowledge regarding mucosal Tregs in both health and disease.

CD101 genetic variants modify regulatory and conventional T cell phenotypes and functions.

We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

Pre-exposure prophylaxis differentially alters circulating and mucosal immune cell activation in herpes simplex virus type 2 seropositive women.

OBJECTIVE: Oral tenofovir-based pre-exposure prophylaxis (PrEP) is an important tool for prevention of new HIV infections, which also reduces subclinical herpes simplex virus type 2 (HSV-2) shedding and symptomatic lesions in HIV-negative, HSV-2-seropositive individuals. However, the impact of PrEP on mucosal immunity has not been examined in detail. DESIGN: Here we evaluate paired genital tissue and systemic immune profiles to characterize the immunological effects of PrEP in HIV-negative, HSV-2-seropositive African women sexually exposed to HIV. METHODS: We compared local and systemic innate and T-cell characteristics in samples collected during PrEP usage and 2 months after PrEP discontinuation. RESULTS: We found that frequencies of cervical CCR5CD4 cells, regulatory T cells, and tissue macrophages were significantly reduced during PrEP use compared with after PrEP discontinuation. In contrast, peripheral blood CD4 and CD8 T cells expressing markers of activation and trafficking were increased during PrEP usage. CONCLUSION: Together, our data are consistent with PrEP altering immunity differentially in the female genital tract compared with circulation in HSV-2+ women. Further study including comparison with HSV-2 negative women is needed to define the overall impact and mechanisms underlying these effects. These results point to the critical need to study the human mucosal compartment to characterize immune responses to mucosal infections.

The Immune Fulcrum: Regulatory T Cells Tip the Balance Between Pro- and Anti-inflammatory Outcomes upon Infection.

Regulatory T cells (Tregs) are indispensable for immune homeostasis and the prevention of autoimmunity. In the context of infectious diseases, Tregs are multidimensional. Here, we describe how they may potentiate effector responses by assisting in recruitment of T cells into the infection site to resolve infection, facilitate accelerated antigen-specific memory responses, limit pathology, and contribute to disease resolution and healing, to the great benefit of the host. We also explore the villainous functions of Tregs during infection by reviewing several diseases in which the depletion or reduction in Treg frequency allows for better generation of effector memory, and results in acute resolution of infection, as opposed to chronicity or severe long-term outcomes. We describe findings generated using mouse models of infection as well as experiments performed using human cells and tissues. We propose that Tregs represent an immunologic fulcrum, promoting both pathogen clearance and damage control by preventing excessive destruction of infected tissues though unchecked immune responses.

Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection.

HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORγt, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI) tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-γ, MIP1-ß, and TNF-α, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR γt suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear.

Limited HIV infection of central memory and stem cell memory CD4+ T cells is associated with lack of progression in viremic individuals.

A rare subset of HIV-infected individuals, designated viremic non-progressors (VNP), remain asymptomatic and maintain normal levels of CD4+ T-cells despite persistently high viremia. To identify mechanisms potentially responsible for the VNP phenotype, we compared VNPs (average >9 years of HIV infection) to HIV-infected individuals who have similar CD4+ T-cell counts and viral load, but who are likely to progress if left untreated ("putative progressors", PP), thus avoiding the confounding effect of differences related to substantial CD4+ T cell depletion. We found that VNPs, compared to PPs, had preserved levels of CD4+ stem cell memory cells (TSCM (p<0.0001), which was associated with decreased HIV infection of these cells in VNPs (r = -0.649, p = 0.019). In addition, VNPs had decreased HIV infection in CD4+ central memory (TCM) cells (p = 0.035), and the total number of TCM cells was associated with increased proliferation of memory CD4+ T cells (r = 0.733, p = 0.01). Our results suggest that, in HIV-infected VNPs, decreased infection of CD4+ TCM and TSCM, cells are involved in preservation of CD4+ T cell homeostasis and lack of disease progression despite high viremia.

HIV vaccine trial exploits a dual and central role for innate immunity.

Limited understanding of correlates of protection from HIV transmission hinders development of an efficacious vaccine. D. J. M. Lewis and colleagues (J. Virol. 88:11648-11657, 2014, doi:10.1128/JVI.01621-14) now report that vaginal immunization with an HIVgp140 vaccine linked to the 70-kDa heat shock protein downregulated the human immunodeficiency virus (HIV) coreceptor CCR5 (chemokine [C-C motif] receptor 5) and increased expression of the HIV resistance factor APOBEC3G (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G), in women. These effects correlated with HIV suppression ex vivo. Thus, vaccine-induced innate responses not only facilitate adaptive immunity-they may prove to be critical for preventing HIV transmission.