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

Human CD4+ T cells, activated by allogeneic monocytes in a primary mixed lymphocyte reaction in the presence of exogenous interleukin (IL) 10, specifically failed to proliferate after restimulation with the same alloantigens. A comparable state of T cell unresponsiveness could be induced by activation of CD4+ T cells by cross-linked anti-CD3 monoclonal antibodies (mAbs) in the presence of exogenous IL-10. The anergic T cells failed to produce IL-2, IL-5, IL-10, interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-10-induced anergic state was long-lasting. T cell anergy could not be reversed after restimulation of the cells with anti-CD3 and anti-CD28 mAbs, although CD3 and CD28 expression was normal. In addition, restimulation of anergized T cells with anti-CD3 mAbs induced normal Ca2+ fluxes and resulted in increased CD3, CD28, and class II major histocompatibility complex expression, indicating that calcineurin-mediated signaling occurs in these anergic cells. However, the expression of the IL-2 receptor alpha chain was not upregulated, which may account for the failure of exogenous IL-2 to reverse the anergic state. Interestingly, anergic T cells and their nonanergic counterparts showed comparable levels of proliferation and cytokine production after activation with phorbol myristate acetate and Ca2+ ionophore, indicating that a direct activation of a protein kinase C-dependent pathway can overcome the tolerizing effect of IL-10. Taken together, these data demonstrate that IL-10 induces T cell anergy and therefore may play an important role in the induction and maintenance of antigen-specific T cell tolerance.

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T1212 Upregulation of E3 Ubiquitin Ligases Related to T Cell Anergy in CD4+ T Cells Isolated from Patients with Ulcerative Colitis in Remission

Gastroenterology ◽

10.1016/s0016-5085(08)62369-0 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-508

Author(s):

Satoshi Egawa ◽

Hideki Iijima ◽

Shinichiro Shinzaki ◽

Sachiko Nakajima ◽

Jumpei Kondo ◽

...

Keyword(s):

Ulcerative Colitis ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Ubiquitin Ligases ◽

E3 Ubiquitin Ligases ◽

T Cell Anergy ◽

Cell Anergy

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T cell anergy in perinatal mice is promoted by T reg cells and prevented by IL-33

Journal of Experimental Medicine ◽

10.1084/jem.20182002 ◽

2019 ◽

Vol 216 (6) ◽

pp. 1328-1344 ◽

Cited By ~ 8

Author(s):

Jonatan Tuncel ◽

Christophe Benoist ◽

Diane Mathis

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

High Expression ◽

T Cell Anergy ◽

Tissue Antigens ◽

Cell Anergy ◽

Deficient Mice

Perinatal T cells broadly access nonlymphoid tissues, where they are exposed to sessile tissue antigens. To probe the outcome of such encounters, we examined the defective elimination of self-reactive clones in Aire-deficient mice. Nonlymphoid tissues were sequentially seeded by distinct waves of CD4+ T cells. Early arrivers were mostly Foxp3+ regulatory T (T reg) cells and metabolically active, highly proliferative conventional T cells (T conv cells). T conv cells had unusually high expression of PD-1 and the IL-33 receptor ST2. As T conv cells accumulated in the tissue, they gradually lost expression of ST2, ceased to proliferate, and acquired an anergic phenotype. The transition from effector to anergic state was substantially faster in ST2-deficient perinates, whereas it was abrogated in IL-33–treated mice. A similar dampening of anergy occurred after depletion of perinatal T reg cells. Attenuation of anergy through PD-1 blockade or IL-33 administration promoted the immediate breakdown of tolerance and onset of multiorgan autoimmunity. Hence, regulating IL-33 availability may be critical in maintaining T cell anergy.

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Impact of simian immunodeficiency virus (SIV) infection on lymphocyte numbers and T-cell turnover in different organs of rhesus monkeys

Blood ◽

10.1182/blood-2002-06-1644 ◽

2003 ◽

Vol 101 (4) ◽

pp. 1213-1219 ◽

Cited By ~ 60

Author(s):

Sieghart Sopper ◽

Dagmar Nierwetberg ◽

Astrid Halbach ◽

Ursula Sauer ◽

Carsten Scheller ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hiv Infection ◽

Simian Immunodeficiency Virus ◽

Cd4 T Cells ◽

Cd4 Counts ◽

Immunodeficiency Virus ◽

Total Body ◽

Spleen And Lymph Nodes ◽

Asymptomatic Phase

HIV infection leads to reduced numbers and increased turnover of CD4+ T cells in blood. However, blood represents only 2% of the total lymphocyte pool, and information about other organs is lacking, leading to controversy about the effects of HIV infection on T-cell homeostasis. Therefore, we have determined phenotype and turnover of lymphocyte subsets in various tissues of macaques. Infection with simian immunodeficiency virus (SIV) resulted in increased proliferation rates of T cells in all organs. Despite reduced CD4 counts in blood, absolute numbers of CD4+ T cells were increased in spleen and lymph nodes and remained stable in nonlymphoid organs such as liver, lung, bone marrow, and brain during the asymptomatic phase, indicative for an altered tissue distribution. In animals killed with first signs of AIDS, total body CD4 counts and proliferation rates had returned to control levels, whereas thymocytes were almost completely absent. Our data show that a drastically increased turnover in the early stages of HIV infection, driven by a generalized immune activation rather than a homeostatic response to CD4+ T-cell destruction, is followed by exhaustion of the regenerative capacity of the immune system.

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Severe Depletion of Mucosal CD4+T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys

The Journal of Immunology ◽

10.4049/jimmunol.179.5.3026 ◽

2007 ◽

Vol 179 (5) ◽

pp. 3026-3034 ◽

Cited By ~ 207

Author(s):

Shari N. Gordon ◽

Nichole R. Klatt ◽

Steven E. Bosinger ◽

Jason M. Brenchley ◽

Jeffrey M. Milush ◽

...

Keyword(s):

T Cells ◽

Simian Immunodeficiency Virus ◽

Cd4 T Cells ◽

Immunodeficiency Virus ◽

Sooty Mangabeys

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Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2010.0972 ◽

2010 ◽

Vol 277 (1701) ◽

pp. 3773-3781 ◽

Cited By ~ 14

Author(s):

Ming Liang Chan ◽

Janka Petravic ◽

Alexandra M. Ortiz ◽

Jessica Engram ◽

Mirko Paiardini ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cell Number ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Proliferating Cells ◽

Immunodeficiency Virus ◽

Sooty Mangabeys

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, ‘natural hosts’ of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to ‘fuel the fire’ of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.

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Simian Immunodeficiency Virus (SIV) Infection Influences the Level and Function of Regulatory T Cells in SIV-Infected Rhesus Macaques but Not SIV-Infected Sooty Mangabeys

Journal of Virology ◽

10.1128/jvi.00026-07 ◽

2007 ◽

Vol 81 (9) ◽

pp. 4445-4456 ◽

Cited By ~ 55

Author(s):

L. E. Pereira ◽

F. Villinger ◽

N. Onlamoon ◽

P. Bryan ◽

A. Cardona ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Acute Infection ◽

T Cell Response ◽

Immunodeficiency Virus ◽

Sooty Mangabeys ◽

Siv Infection

ABSTRACT Differences in clinical outcome of simian immunodeficiency virus (SIV) infection in disease-resistant African sooty mangabeys (SM) and disease-susceptible Asian rhesus macaques (RM) prompted us to examine the role of regulatory T cells (Tregs) in these two animal models. Results from a cross-sectional study revealed maintenance of the frequency and absolute number of peripheral Tregs in chronically SIV-infected SM while a significant loss occurred in chronically SIV-infected RM compared to uninfected animals. A longitudinal study of experimentally SIV-infected animals revealed a transient increase in the frequency of Tregs from baseline values following acute infection in RM, but no change in the frequency of Tregs occurred in SM during this period. Further examination revealed a strong correlation between plasma viral load (VL) and the level of Tregs in SIV-infected RM but not SM. A correlation was also noted in SIV-infected RM that control VL spontaneously or in response to antiretroviral chemotherapy. In addition, immunofluorescent cell count assays showed that while Treg-depleted peripheral blood mononuclear cells from RM led to a significant enhancement of CD4+ and CD8+ T-cell responses to select pools of SIV peptides, there was no detectable T-cell response to the same pool of SIV peptides in Treg-depleted cells from SIV-infected SM. Our data collectively suggest that while Tregs do appear to play a role in the control of viremia and the magnitude of the SIV-specific immune response in RM, their role in disease resistance in SM remains unclear.

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