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Relative Resistance in the Development of T Cell Anergy in CD4⁺ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys¹

Pavel Bostik^2,*, Ann E. Mayne^*, Francois Villinger^*, Kenneth P. Greenberg^*, Jonathan D. Powell and Aftab A. Ansari^*

^* Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; and Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

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.

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