Dataset Information

Cytotoxic T Cell Functions Accumulate When CD4 Is Downregulated by CD4+ T Cells in African Green Monkeys.

ABSTRACT: African green monkeys (AGMs) are a natural host of SIV that do not develop simian AIDS. Adult AGMs naturally have low numbers of CD4+ T cells and a large population of MHC class II-restricted CD8?? T cells that are generated through CD4 downregulation in CD4+ T cells. In this article, we study the functional profiles and SIV infection status in vivo of CD4+ T cells, CD8?? T cells, and CD8?? T cells in lymph nodes, peripheral blood, and bronchoalveolar lavage fluid of AGMs and rhesus macaques (in which CD4 downregulation is not observed). We show that, although CD8?? T cells in AGMs maintain functions associated with CD4+ T cells (including Th follicular functionality in lymphoid tissues and Th2 responses in bronchoalveolar lavage fluid), they also accumulate functions normally attributed to canonical CD8+ T cells. These hyperfunctional CD8?? T cells are found to circulate peripherally, as well as reside within the lymphoid tissue. Due to their unique combination of CD4 and CD8 T cell effector functions, these CD4- CD8?? T cells are likely able to serve as an immunophenotype capable of Th1, follicular Th, and CTL functionalities, yet they are unable to be infected by SIV. These data demonstrate the ambiguity of CD4/CD8 expression in dictating the functional capacities of T cells and suggest that accumulation of hyperfunctional CD8?? T cells in AGMs may lead to tissue-specific antiviral immune responses in lymphoid follicles that limit SIV replication in this particular anatomical niche.

SUBMITTER: Vinton CL

PROVIDER: S-EPMC5502537 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Cytotoxic T Cell Functions Accumulate When CD4 Is Downregulated by CD4+ T Cells in African Green Monkeys.

Vinton Carol L CL Ortiz Alexandra M AM Calantone Nina N Mudd Joseph C JC Deleage Claire C Morcock David R DR Whitted Sonya S Estes Jacob D JD Hirsch Vanessa M VM Brenchley Jason M JM

Journal of immunology (Baltimore, Md. : 1950) 20170424 11

African green monkeys (AGMs) are a natural host of SIV that do not develop simian AIDS. Adult AGMs naturally have low numbers of CD4+ T cells and a large population of MHC class II-restricted CD8αα T cells that are generated through CD4 downregulation in CD4+ T cells. In this article, we study the functional profiles and SIV infection status in vivo of CD4+ T cells, CD8αα T cells, and CD8αβ T cells in lymph nodes, peripheral blood, and bronchoalveolar lavage flui ...[more]

PMID: 28438898

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Project description:UnlabelledAfrican green monkeys (AGMs; genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIVAGM). As they do not develop simian AIDS, there is great interest in understanding how this species has evolved to avoid immunodeficiency. Adult African green monkeys naturally have low numbers of CD4 T cells and a large population of major histocompatibility complex class II-restricted CD8α(dim) T cells that are generated through CD4 downregulation in CD4(+) T cells. Mechanisms that drive this process of CD4 downregulation are unknown. Here, we show that juvenile AGMs accelerate CD4-to-CD8αα conversion upon SIV infection and avoid progression to AIDS. The CD4 downregulation induced by SIV infection is not limited to SIV-specific T cells, and vaccination of an adult AGM who had a negligible number of CD4 T cells demonstrated that CD4 downregulation can occur without antigenic exposure. Finally, we show that the T cell homeostatic cytokines interleukin-2 (IL-2), IL-7, and IL-15 can induce CD4 downregulation in vitro. These data identify a mechanism that allows AGMs to generate a large, diverse population of T cells that perform CD4 T cell functions but are resistant to SIV infection. A better understanding of this mechanism may allow the development of treatments to induce protective CD4 downregulation in humans.ImportanceMany African primate species are naturally infected with SIV. African green monkeys, one natural host species, avoid simian AIDS by creating a population of T cells that lack CD4, the human immunodeficiency virus/SIV receptor; therefore, they are resistant to infection. However, these T cells maintain properties of CD4(+) T cells even after receptor downregulation and preserve immune function. Here, we show that juvenile AGMs, who have not undergone extensive CD4 downregulation, accelerate this process upon SIV infection. Furthermore, we show that in vivo, CD4 downregulation does not occur exclusively in antigen-experienced T cells. Finally, we show that the cytokines IL-2, IL-7, and IL-15, which induce homeostatic T cell proliferation, lead to CD4 downregulation in vitro; therefore, they can provide signals that lead to antigen-independent CD4 downregulation. These results suggest that if a similar process of CD4 downregulation could be induced in humans, it could provide a cure for AIDS.

Dataset Information

Cytotoxic T Cell Functions Accumulate When CD4 Is Downregulated by CD4+ T Cells in African Green Monkeys.

Publications

Cytotoxic T Cell Functions Accumulate When CD4 Is Downregulated by CD4<sup>+</sup> T Cells in African Green Monkeys.

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