An African green monkey lacking peripheral CD4 lymphocytes that retains helper T cell activity and coexists with SIVagm

Murayama, Yuichi; Mukai, Ryozaburo; Inoue‐Murayama, Miho; Yoshikawa, Yasuhiro

doi:10.1046/j.1365-2249.1999.00999.x

Cited by 32 publications

(36 citation statements)

References 44 publications

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“…Consistent with previous studies (7,25), the SIV Gag-specific T cell response was not of exceptional magnitude, and the immune response to SIV clearly was not able to fully control viremia in the study animals. Instead, it is clear that natural host species are able to avoid progressive disease despite ongoing viral replication.…”

Section: Discussionsupporting

confidence: 89%

“…Adult AGMs have low CD4 ϩ T cell counts (4,5) and a large population of CD8␣ dim T cells that express CD8␣␣ homodimers and are distinct from the classical CD8 T cells that express the ␣ and ␤ chain of CD8 (4,6,7). These CD8␣␣ T cells arise postthymically through CD4 downregulation by CD4 ϩ T cells (4).…”

mentioning

confidence: 99%

“…Downregulation on some CD4 ϩ T cells can be induced in vitro by stimulatory signals, such as mitogens or superantigens, that stimulate through the T cell receptor (4,6,7), but it remains unknown why some dividing cells downregulate CD4 while others maintain expression. In vivo, nearly all CD8␣␣ T cells have a memory phenotype (4), so it is thought that CD4 downregulation may be driven by cellular maturation.…”

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confidence: 99%

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Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

Perkins

Briant

Calantone

et al. 2014

J Virol

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African green monkeys (AGMs; genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIV AGM ). 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 CD8␣ 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-CD8␣␣ 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. IMPORTANCE Many 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.

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

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confidence: 99%

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Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

Perkins

Briant

Calantone

et al. 2014

J Virol

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“…Furthermore, in some contexts, CD8 dim T cells substituted for CD4 + T cells and provided B cell help, leading to antibody production (48,49). Other studies showed that type 2 polarization of CD8 + T cells induced epigenetic modifications on the CD8α locus, resulting in downregulation of CD8 surface expression in mice (32).…”

Section: Consistent With Our Findings Are Reports That Cd8mentioning

confidence: 99%

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Falanga¹,

Frascoli²,

Kaymaz³

et al. 2017

JCI Insight

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Cellular and humoral constituents of the immune system differ significantly between children and adults, yet very little is known about the impact of early-life pathogen exposure on this immunologic transition. We examined CD4+ and CD8+ T cell subsets defined by CCR7 and CD45RA expression in two longitudinal pediatric cohorts experiencing divergent levels of pathogen burden. Using multiparameter flow cytometry, along with serological, cytokine, and transcriptomic data, we show that cumulative pathogen burden promotes the development of atypical CD8dim T cells with an innate-like profile (Granzyme Bhi, IFNγlow, TNFαlow, PLFZhi, ID2hi, IKZF2hi) in contrast to age-matched children residing in a low pathogen-exposure area who display a more conventional CD8bright profile (IFNγ+, TNFα+, CCL4+). Furthermore, these unconventional T cells had stunted proliferation, distinct transcriptional programs, and impaired T cell receptor signaling and were enriched in hallmark TNFα, NF-κB, and IL-6 gene signaling pathways, reminiscent of NK cells and type-1 innate lymphoid cells. Our findings suggest that these unconventional CD8dim T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses

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“…It is possible that HIV-1 may be able to infect other lymphoid cells through a CD4-independent mechanism (as has been suggested for the infection of astrocytes in the central nervous system), or it may target cells that transiently express CD4 during maturation or activation. Many investigators have provided evidence for the widespread infection in vitro and in vivo of human CD8 ϩ , cytotoxic T lymphocytes by HIV-1 (16,30,32,34,50,54) or by the primate simian immunodeficiency virus (SIV) homologues SIV mac in sooty mangabeys (12) and SIV agm in African green monkeys (37). Infection of cells destined to become CD8 lymphocytes may occur through a conventional CD4-dependent mechanism during their maturation in the thymus, at the stage where CD4 is coexpressed with CD8 (12,24).…”

mentioning

confidence: 99%

Activated Peripheral CD8 Lymphocytes Express CD4 In Vivo and Are Targets for Infection by Human Immunodeficiency Virus Type 1

Imlach

McBreen

Shirafuji

et al. 2001

J Virol

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There is increasing evidence that CD8 lymphocytes may represent targets for infection by human immunodeficiency virus type 1 (HIV-1) in vivo whose destruction may contribute to the loss of immune function underlying AIDS. HIV-1 may infect thymic precursor cells destined to become CD4 and CD8 lymphocytes and contribute to the numerical decline in both subsets on disease progression. There is also evidence for the induction of CD4 expression and susceptibility to infection by HIV-1 of CD8 lymphocytes activated in vitro. To investigate the relationship between CD8 activation and infection by HIV-1 in vivo, activated subsets of CD8 lymphocytes in peripheral blood mononuclear cells (PBMCs) of HIV-seropositive individuals were investigated for CD4 expression and HIV infection. Activated CD8 lymphocytes were identified by expression of CD69, CD71, and the human leukocyte antigen (HLA) class II, the ␤-chain of CD8, and the RO isoform of CD45. CD4؉ and CD4 ؊ CD8 lymphocytes, CD4 lymphocytes, other T cells, and non-T cells were purified using paramagnetic beads, and proviral sequences were quantified by PCR using primers from the long terminal repeat region. Frequencies of activated CD8 lymphocytes were higher in HIV-infected study subjects than in seronegative controls, and they frequently coexpressed CD4 (mean frequencies on CD69 ؉ , CD71 ؉ , and HLA class II ؉ cells of 23, 37, and 8%, respectively, compared with 1 to 2% for nonactivated CD8 lymphocytes). The level of CD4 expression of the double-positive population approached that of mature CD4 lymphocytes. That CD4 expression renders CD8 cell susceptible to infection was indicated by their high frequency of infection in vivo; infected CD4 ؉ CD8 lymphocytes accounted for between 3 and 72% of the total proviral load in PBMCs from five of the eight study subjects investigated, despite these cells representing a small component of the PBMC population (<3%). Combined, these findings provide evidence that antigenic stimulation of CD8 lymphocytes in vivo induces CD4 expression that renders them susceptible to HIV infection and destruction. The specific targeting of responding CD8 lymphocytes may provide a functional explanation for the previously observed impairment of cytotoxic T-lymphocyte (CTL) function disproportionate to their numerical decline in AIDS and for the deletion of specific clones of CTLs responding to HIV antigens.

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An African green monkey lacking peripheral CD4 lymphocytes that retains helper T cell activity and coexists with SIVagm

Cited by 32 publications

References 44 publications

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Activated Peripheral CD8 Lymphocytes Express CD4 In Vivo and Are Targets for Infection by Human Immunodeficiency Virus Type 1

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