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CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.

International audience; A variety of signals influence the capacity of dendritic cells (DCs) to mount potent antiviral cytotoxic T-cell (CTL) responses. In particular, innate immune sensing by pathogen recognition receptors, such as TLR and C-type lectines, influences DC biology and affects their susceptibility to HIV infection. Yet, whether the combined effects of PPRs triggering and HIV infection influence HIV-specific (HS) CTL responses remain enigmatic. Here, we dissect the impact of innate immune sensing by pathogen recognition receptors on DC maturation, HIV infection, and on the quality of HS CTL activation. Remarkably, ligand-driven triggering of TLR-3, -4, NOD2, and DC-SIGN, despite reducing viral replication, markedly increased the capacity of infected DCs to stimulate HS CTLs. This was exemplified by the diversity and the quantity of cytokines produced by HS CTLs primed by these DCs. Infecting DCs with viruses harboring members of the APOBEC family of antiviral factors enhanced the antigen-presenting skills of infected DCs. Our results highlight the tight interplay between innate and adaptive immunity and may help develop innovative immunotherapies against viral infections.

HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. How these HIV-specific cells avoid infection and depletion upon encounter with the virus remains incompletely understood. Ex vivo characterization of single Gag-specific CD4 + T cells reveals an advanced Th1 differentiation pattern in controllers, except for the CCR5 marker, which is downregulated compared to specific cells of treated patients. Accordingly, controller specific CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry. Two controllers carried biallelic mutations impairing CCR5 surface expression, indicating that in rare cases CCR5 downregulation can have a direct genetic cause. Increased expression of β-chemokine ligands upon high-avidity antigen/TCR interactions contributes to autocrine CCR5 downregulation in controllers without CCR5 mutations. These findings suggest that genetic and functional regulation of the primary HIV coreceptor CCR5 play a key role in promoting natural HIV control., Here, Claireaux et al. show that people who naturally control HIV infection express lower levels of the viral co-receptor CCR5 in specific CD4+ T cells, and that this results from mutations or receptor internalization by CD4+ T cell-produced chemokines.

Introduction La physiopathologie de l’hidradenite suppuree (HS) est mal comprise. Les cellules dendritiques (DC), a l’interface entre l’immunite innee et adaptative, pourraient faire le lien entre l’environnement notamment bacterien de la flore commensale et le recrutement chronique de lymphocytes T. La caracterisation des sous-populations de DC n’a jamais ete faite dans cette pathologie. Nous avons caracterise les DC cutanees et circulantes de HS en comparant a des temoins (HD). Materiel et methodes L’etude reposait sur un CCP avec consentement ecrit des patients. Tous les patients HS inclus (n = 5 peau, n = 10 sang) ne prenaient aucun traitement immunomodulateur et presentaient des stades Hurley et phenotypes LC differents. Les sous-types de DC marquees par differents panels d’anticorps etaient analyses au cytometre en flux. Etaient caracterisees dans la peau, les cellules de Langherans (LC), les DC epidermiques (eDC), les DC dermiques (dDC), les DC plasmacytoides (pDC), et dans le sang les pDC et les DC issues de monocytes (mDC) CD1c+ et CD141+. L’analyse statistique etait faite par Mann-Whitney U test. Resultats Dans la peau, la frequence de pDC etait significativement augmentee dans l’epiderme HS compare au HD (7,03 % vs 0,22 %, p = 0,004). A l’inverse, les LC et dDC etaient diminuees (respectivement, moyenne : 22,23 % versus 83 %, p = 0,003 et 4,21 % vs 65,44 %, p = 0,03). La frequence des eDC n’etait pas differente (3,18 % vs 1,54 %, p = 0,23). Dans le sang, la frequence des pDC etait significativement diminuee chez les HS (moyenne : 0,18 % vs 0,60 %, p = 0,009). Les mDC CD1c+ et mDC CD141+ etaient egalement diminuees chez les HS (respectivement, moyenne 0,27 % vs 0,49 % p = 0,043, et 0,06 % vs 0,19 %, p = 0,042). Au total, la frequence des pDC dans l’epiderme etait significativement augmentee chez les HS et diminuee dans leur sang ( Fig. 1 et 2 ). Discussion Nous retrouvons un infiltrat cutane de pDC probablement recrutees a partir du sang. En effet, les resultats du laboratoire montrent une secretion spontanee d’IP-10 et RANTES par les ORS, cellules souches du follicule pileux, des patients HS. Ces chemokines pourraient etre a l’origine du recrutement des pDC. Ces pDC activees par les produits microbiens secreteraient de l’IFN type 1 entrainant un environnement pro-inflammatoire. Celui-ci accentuerait l’activation des ORS creant ainsi un cercle vicieux a l’origine de l’inflammation chronique observee dans l’HS. Conclusion L’infiltration significative de pDC dans la peau pourrait etre au centre de la physiopathologie de l’HS par l’installation d’un environnement IFN type 1. Compte tenu de l’absence d’efficacite a long terme des traitements utilises en pratique courante, nous pourrions envisager a terme des traitements ciblant la voie de l’IFN type 1 dans l’HS.