TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

Abstract

SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8 þ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8 þ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-b and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8 þ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8 þ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/ memory CD8 þ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1 þ expressing cells. Finally, we provide evidence that abrogation of TGF-b in vitro enhances T-cell proliferation and reduces CD8 þ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS. Cell Death and Differentiation (2007) 14, 1747-1758; doi:10.1038/sj.cdd.4402192; published online 6 July 2007Virus production in Human Immunodeficiency Virus 1 (HIV-1)-infected individuals is largely the result of a dynamic process involving continuous rounds of de novo infection and replication in CD4 þ cells with rapid turnover of both free virus and virus producing cells. Moreover, an increasing body of evidence suggests that reservoirs, cell types or anatomical sites ('sanctuaries'), represent a major barrier to virus eradication. 1 HIV-specific CD8 þ T lymphocytes (CTL) are considered crucial in the control of viral replication. 2 Excessive induction of apoptosis has been proposed as one major mechanism of abnormal T-cell response during HIV and Simian Immunodeficiency Virus (SIV) infections. 3 However, most studies, which investigated the potential relationship between HIV and SIV infections and apoptosis have focused on cells from peripheral blood, rather than on cells from lymphoid organs.Peripheral lymphoid tissues such as the axillary and inguinal (Ing) lymph nodes (LNs), which drain the arms and legs, respectively, and the spleen, are considered major sites of HIV/SIV replication. 4 Accumulating data also indicate that gut-associated lymphoid tissue (GALT), which contains inductive sites, Peyer's patches and mesenteric (Mes) LNs, and effectors sites located within lamina propria and epithelium of the intestinal wall, is also an early and predominant tissue site of viral replication and may be a reservoir for HIV/SIV. 5,6 Because T cells from the GALT are required to maintain a state of immunological tolerance toward a myriad of dietary and resident bacterial antigens, the chronic exposure of HIV/ SIV-specific antigens coul...

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…However, infection of Treg cells with HIV represses Foxp3 expression, reduces the generation of TGF-b, and increases IL-4 production, thus limiting Treg-cell function (Pion et al 2013) and likely contributing to chronic inflammation seen in HIV-infected patients. TGF-b produced in the mucosal lymph nodes during HIV infection can also induce apoptosis of activated CD8 þ T cells (Cumont et al 2007), whereas promoting the generation of NKT cells, which share properties of both T cells and NK cells, which produce IL-17 (Campillo-Gimenez et al 2010). Furthermore, the HIV envelope protein gp120 can bind to a4b7 integrins on naïve B cells to induce TGF-b and Fc receptor-like 4 (FcRL4) expression, which causes B-cell dysfunction and inhibits their proliferation (Jelicic et al 2013).…”

AIDS Progression Is Associated with the Emergence of IL-17–Producing Cells Early After Simian Immunodeficiency Virus Infection

“…The elevation of TGF-b (15)(16)(17) plus an inflammatory environment may suggest the possible induction of Th17 population in this context. However, recent reports indicated a lower frequency of Th17 CD4 + T cells at mucosal and systemic sites during HIV infection and SIV infection (18)(19)(20)(21).…”

Apoptose et Sida, une affaire d’intégration ?

“…Le virus chercherait-il à rendre anergique la réponse CD4, voire à minimiser celle-ci afin de lui permettre une meilleure dissé-mination et survie ? Ainsi, la localisation du virus dans des sites où la réponse immunitaire est effectivement hautement contrôlée comme l'intestin représente-t-elle une stratégie d'échappement à la réponse immune ou bien une manière de se tapir dans des sanctuaires privilégiés à faible niveau d'activation [21,22] …”