CD25⁺Regulatory T Cells Isolated from HIV-Infected Individuals Suppress The Cytolytic And Nonlytic Antiviral Activity of HIV-specific CD8⁺T Cells in Vitro

Abstract

HIV infection is characterized by CD4(+) T cell depletion and progressive immune dysfunction; particularly impacted are HIV-specific T cell responses. An important component of immune-mediated control of HIV replication, killing of infected cells, appears to be impaired, in part due to poor cytolytic activity of HIV-specific cytotoxic T cells (CTL). In vitro, several functions of HIV-specific T cells, such as cytokine production, can be enhanced by the depletion of the immunosuppressive CD25(+) FoxP3(+) CD4(+) regulatory (Treg) cell subset. However, the effect of CD25(+) Treg cells on virus-specific cytolytic activity in the context of HIV or any human viral infection has not been investigated. The present study demonstrates that CD25(+) Treg cells isolated from the peripheral blood of HIV-infected subjects significantly suppress HIV Gag-specific cytolytic activity in vitro. In addition, CD25(+) Treg cells suppress effector function (coexpression of TNF-alpha and IFN-gamma) of HIV-specific CD8(+) T cells that proliferate in response to HIV antigen. Finally, the secretion of HIV-inhibitory CC-chemokines by HIV-specific and nonspecific CD8(+) T cells is significantly reduced in the presence of CD25(+) Treg cells. These data suggest that CD25(+) Treg-mediated suppression of the antiviral activity of HIV-specific CD8(+) T cells could impact the ability of HIV-infected individuals to control HIV replication in vivo.

T Regulatory Cells Contribute to the Attenuated Primary CD8+ and CD4+ T Cell Responses to Herpes Simplex Virus Type 2 in Neonatal Mice

“…A number of microbial pathogens including viruses have been previously shown to increase the frequency of Tregs in infected tissues or lymphoid organs of adult mice and humans (12,(52)(53)(54)(55)(56). CD4 ϩ CD25 ϩ Tregs have been shown to suppress CD8 ϩ T effector function and activation to viruses including HSV and to viral vaccines in adult humans ex vivo, and in adult mice in vitro and in vivo (12,20,(53)(54)(55)(56)(57)(58)(59)(60). Enhanced Treg responses have been detected in the cord blood of human neonates born to women with Plasmodium falciparum infection compared with unexposed infants or infants born to mothers who had been treated for malaria (22).…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…The in vitro suppressive capacity of CD4 + Treg cells from HIV‐1 infected individuals is reported to be comparable to that of HIV‐seronegative donors, and CD4 + Treg cells from subjects acutely or chronically infected with HIV‐1 have also been shown to suppress HIV‐specific CD4 + T‐cell proliferation and cytokine production in vitro 274, 275. However, the circulating frequency of CD4 + Treg cells has not been found to show any correlation with the magnitude of HIV‐specific T‐cell responses,276, 277, 278 leaving the contribution of CD4 + Treg cells to regulation of virus‐specific T‐cell responses in HIV‐infected individuals unclear.…”

Endogenous IL-32 Controls Cytokine and HIV-1 Production

“…This T cell subset can suppress both Th1 and Th2 responses, thus preventing excessive immune reactions and autoimmunity (48). However, these properties are detrimental in HIV infection as regulatory T cells impair the antiviral activities of HIV-specific T cells (49) and can enhance HIV-1 gene expression (50). Therefore, IL-32 not only induces the production of cytokines in general and proinflammatory mediators in particular but may also play a role in promoting Th1 differentiation of T cells and a role in the inhibition of regulatory T cell chemotaxis.…”