CD8 ؉ T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8 ؉ T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIVsuppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIVspecific CD8 ؉ T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8 ؉ T cells from infected donors. We report that attributes of CD8 ؉ T-cell effi- IntroductionCD8 ϩ T cells are essential for effective immunity against HIV-1, and the induction of such responses using vaccines has become a major objective in the strategy to halt the pandemic. 1 However, the recent outcome of the Merck STEP study, the most ambitious trial of an anti-HIV T cell-based vaccine conducted to date, has been a major disappointment. 2 Despite its immunogenicity, the vaccine failed both to prevent infection of vaccinated volunteers at high risk of acquiring HIV and to reduce viral load set points in infected vaccinees. This failure has roused the scientific community to step back and reconsider its basic knowledge of T cell-mediated efficacy. 3,4 Indeed, consensual opinion is that our general understanding of T-cell efficacy in HIV-1 infection is actually still limited, which represents a clear obstacle to the design of successful vaccines.Over recent years, qualitative attributes of CD8 ϩ T cells have increasingly become the focus of attempts to identify reliable correlates of immune protection against HIV. Among these, polyfunctionality 5 and HIV-suppressive activity 6 have been associated with spontaneous control of HIV infection and slower disease progression rates in infected patients. Of note, polyfunctionality is currently seen as the best correlate of T-cell efficacy measurable directly ex vivo. 7 Polyfunctional CD8 ϩ T cells are those that exhibit multiple effector functions (ie, degranulation and production of antiviral factors) simultaneously upon antigen encounter; this can be assessed after stimulation with cognate peptides by multiparametric flow cytometry (eg, mobilization of CD107 and intracellular production of interferon [IFN]-␥, tumor necrosis factor [TNF]-␣, interleukin-2 [IL-2], and macrophage-inflammatory protein [MIP]-1␤). 5 HIV-suppressive activity reflects the capacity of HIV-specific CD8 ϩ T cells to eliminate HIV-infected targets via classical class I major histocompatibility complex (MHC)-restricted cytotoxic lysis. 6,8 It can be assessed using primary CD4 ϩ T cells infected in vitro with HIV in the presence of...

Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and auto immunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typi cally beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the fore front of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks.

While the thymus is known to be essential for the initial production of T cells during early life, its contribution to immune development remains a matter of debate. In fact, during cardiac surgery in newborns, the thymus is completely resected to enable better access to the heart to correct congenital heart defects, suggesting that it may be dispensable during childhood and adulthood. Here, we show that young adults thymectomized during early childhood exhibit an altered T cell compartment. Specifically, absolute CD4 + and CD8 + T cell counts were decreased, and these T cell populations showed substantial loss of naive cells and accumulation of oligoclonal memory cells. A subgroup of these young patients (22 years old) exhibited a particularly altered T cell profile that is usually seen in elderly individuals (more than 75 years old). This condition was directly related to CMV infection and the induction of strong CMV-specific T cell responses, which may exhaust the naive T cell pool in the absence of adequate T cell renewal from the thymus. Together, these marked immunological alterations are reminiscent of the immune risk phenotype, which is defined by a cluster of immune markers predictive of increased mortality in the elderly. Overall, our data highlight the importance of the thymus in maintaining the integrity of T cell immunity during adult life.

PD-1 expression on CD8 T cells, including those specific for HIV, can be related both to their differentiation stage and their activation status. It is important to consider these findings when assessing the expression of PD-1 on T cells.

The mechanisms of CD4+ T-cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion of CD4+ T cells occurs during the course of HIV-1 infection, so that maintenance of adequate CD4+ T-cell levels probably depends primarily on the capacity to renew depleted lymphocytes, that is, the lymphopoiesis. We performed here a comprehensive study of quantitative and qualitative attributes of CD34+ hematopoietic progenitor cells directly from the blood of a large set of HIV-infected persons compared with uninfected donors, in particular the elderly. Our analyses underline a marked impairment of primary immune resources with the failure to maintain adequate lymphocyte counts. Systemic immune activation emerges as a major correlate of altered lymphopoiesis, which can be partially reversed with prolonged antiretroviral therapy. Importantly, HIV disease progression despite elite control of HIV replication or virologic success on antiretroviral treatment is associated with persistent damage to the lymphopoietic system or exhaustion of lymphopoiesis. These findings highlight the importance of primary hematopoietic resources in HIV pathogenesis and the response to antiretroviral treatments.

Immunopathogenesis of Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is poorly known. In previous studies, various cytokines were detected in ECD lesions, presumably orchestrating lesional histiocyte recruitment. Because ECD lesions are frequently associated with systemic symptoms, we postulated that underlying global immune perturbations might also be revealed. We quantitatively analyzed 23 cytokines in serum samples obtained from a large single-center cohort of 37 patients with ECD, and studied the impact of treatment on cytokine production. IL-6, IL-12, interferon-α (IFN-α), and monocyte chemotactic protein-1 (MCP-1) levels were significantly higher in untreated patients than in controls, whereas interferon-γ (IFN-γ) inducible protein 10, IL-12, MCP-1, and IL-1 receptor antagonist were found significantly increased in IFN-α-treated patients. A biomathematical approach was used to rationalize multiparameter data, to generate new hypotheses, and identify global control pathways. Interestingly, cytokine profiles proved to be particularly stable at the individual level, and an "ECD signature" further distinguished patients from controls, based on their production of IFN-α, IL-12, MCP-1, IL-4, and IL-7. Altogether, our data underline the systemic immune Th-1-oriented perturbation associated with this condition and provide clues for the choice of more focused therapeutic agents in this rare disease with noncodified therapeutic management.

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.

Background: Besides intestinal barrier function, the host tolerates gut commensals through both innate and adaptive immune mechanisms. It is now clear that gut commensals induce local immunoglobulin A (IgA) responses, but it remains unclear whether anti-microbiota responses remain confined to the gut. Objective: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions, and in the absence of IgA. Methods: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd) and common variable immunodeficiency (CVID). Immunoglobulincoated bacterial repertoires were analyzed by combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing, and bacterial lysates were probed by western blot analysis with healthy donors serums. Results: Although absent from the healthy gut, serum anti-microbiota IgG are present in healthy individuals, and increased in SIgAd patients. IgG converge with non-overlapping secretory IgA repertoires to target the same bacteria. Each individual targets a diverse, microbiota repertoire whose proportion inversely correlates with systemic inflammation. Finally, Intravenous Immunoglobulin preparations (IVIG) target much less efficiently CVID gut microbiota than healthy microbiota. Conclusion: Secretory IgA is pivotal for induction of tolerance to gut microbiota. SIgAdassociated inflammation is inversely correlated with systemic anti-commensal IgG responses, which may thus serve as a second line of defense. We speculate that SIgAd patients could benefit from oral IgA supplementation. Our data also suggest that IVIG preparations might be supplemented with IgG from IgA deficient patients pools in order to offer a better protection against gut bacterial translocations in CVID. Key Messages:-Systemic IgG and secretory IgA bind a common spectrum of commensals.-Increased proportions of IgG+ microbiota and inflammatory markers in SIgAd.-IVIG poorly target CVID and SIgAd gut microbiota.