Relative Resistance in the Development of T Cell Anergy in CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys

Abstract

Despite high viral loads, T cells from sooty mangabey (SM) monkeys that are naturally infected with SIV but remain clinically asymptomatic, proliferate and demonstrate normal Ag-specific memory recall CD4+ T cell responses. In contrast, CD4+ T cells from rhesus macaques (RM) experimentally infected with SIV lose Ag-specific memory recall responses and develop immunological anergy. To elucidate the mechanisms for these distinct outcomes of lentiviral infection, highly enriched alloreactive CD4+ T cells from humans, RM, and SM were anergized by TCR-only stimulation (signal 1 alone) and subsequently challenged with anti-CD3/anti-CD28 Abs (signals 1 + 2). Whereas alloreactive CD4+T cells from humans and RM became anergized, surprisingly, CD4+ T cells from SM showed marked proliferation and IL-2 synthesis after restimulation. This resistance to undergo anergy was not secondary to a global deficiency in anergy induction of CD4+ T cells from SM since incubation of CD4+ T cells with anti-CD3 alone in the presence of rapamycin readily induced anergy in these cells. The resistance to undergo anergy was reasoned to be due to the ability of CD4+ T cells from SM to synthesize IL-2 when incubated with anti-CD3 alone. Analysis of phosphorylated kinases involved in T cell activation showed that the activation of CD4+ T cells by signal 1 in SM elicited a pattern of response that required both signals 1 + 2 in humans and RM. This function of CD4+ T cells from SM may contribute to the resistance of this species to SIV-induced disease.

CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys Produce More IL-2 Than Cells from Disease-Susceptible Species: Involvement of p300 and CREB at the Proximal IL-2 Promoter in IL-2 Up-Regulation

“…Keeping that in mind, it is therefore reasonable to postulate that in the models of lentivirus infection, which exhibit resistance to the development of AIDS despite significant virus replication, such as SM, at least some of the mechanisms underlying this phenomenon of disease resistance represent general characteristics of the immune system and not specific responses to virus infection. One such characteristic that we described previously is the relative resistance of CD4 ϩ T cells from SM to the experimentally induced anergy (5,16).…”

“…These differential patterns were not secondary to differences in the frequency of naive, central memory, or effector memory CD4 ϩ T cells from the two species (5,16). To further investigate whether at least some of these characteristics could be ascribed to the ability of the CD4 ϩ T cells from SM to produce higher baseline levels of IL-2, which may subsequently contribute to increased survival and well being of cells in the SIV-infected animals, we analyzed baseline IL-2 production in PBMC from RM and SM (Fig.…”

“…Interestingly, the CD4 ϩ T cells from the SIV disease-resistant SM are resistant to the induction of immunological anergy; they show an anergy-resistant phenotype, which was shown to predominantly reside in the central memory CD4 ϩ T cell population (5,16). This phenotype is characterized by their ability to produce significant levels of IL-2 even when stimulated via TCR alone.…”

“…In SIV-infected RM, immunological anergy is detectable in both the CD4 ϩ and CD8 ϩ cells before any detectable signs of CD4 ϩ T cell depletion (6). Interestingly, such loss of CD4 ϩ T cell responses with subsequent AIDS-like pathogenesis does not occur in naturally or experimentally SIV-infected sooty mangabeys (SM) despite significant plasma and cellular viral loads associated with disease progression in Asian macaques (5,7). IL-2 is a key factor in multiple processes involved in the survival of T lymphocytes and in the regulation of T cell responses.…”

“…Increased IL-2 production may be beneficial also to the regulatory T cell subset, which was recently described to express the highaffinity receptor for IL-2, and subsequently contributes to the low apparent immune activation seen in SIV-positive SM (7,17). Previous sequence analysis of the Ϫ180 AP-1-like site from macaques and mangabeys revealed a single nucleotide substitution within this region only in SM that target this regulatory site (5).…”