Timed Ablation of Regulatory CD4+ T Cells Can Prevent Murine AIDS Progression

Abstract

We describe successful immunotherapy of murine AIDS (MAIDS) in C57BL/6J mice based on the elimination of replicating CD4+ regulator T cells. We demonstrate that a single injection of the antimitotic drug vinblastine (Vb) given 14 days postinfection (p.i.) with LP-BM5 can prevent MAIDS progression. Treatment with anti-CD4 mAb at 14 days p.i. is similarly able to prevent MAIDS. Treatment at other time points with Vb or anti-CD4 mAb is ineffective. The effect is based on ablation of a replicating dominantly suppressive CD4+ T cell population, as indicated by adoptive transfer and in vivo depletion experiments using mAbs against CD4 as well as combinations of mAbs against the known regulatory cell surface markers CD25, GITR, and CTLA-4. Cell surface marker analysis shows a population of CD4+CD25+ cells arising shortly before day 14 p.i. Cytokine analyses show a peak in IL-10 production from day 12 to day 16 p.i. MAIDS-infected mice also have CD4+ T cells with significantly higher expression levels of CD38 and particularly CD69, which have been demonstrated to be regulator T cell markers in the Friend retroviral model. The immunotherapy appears to prevent disease progression, although no protection against reinfection with LP-BM5 is generated. These data define a new therapy for murine retroviral infection, which has potential for use in other diseases where T regulator cell-mediated immunosuppression plays a role in the disease process.

Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection

“…Thus, this CD4 + T cell population was associated with suppressive activity during acute FV infection. In addition, it has been reported that the treatment of FV or LP-BM5 retrovirus (which induces mouse AIDS) infected mice with an antibody against GITR, which has been suggested to either block the suppressive function of Treg cells [20], or to make CD8 + T cells refractory to Treg suppression [30], can overcome CD8 + T cell dysfunction and virusinduced immunosuppression [31,32]. Taken together, these findings indicate that CD4 + CD25 -GITR + CD103 + T cells might be an important population of induced Treg in chronic retroviral infection.…”

Murine γ-Herpesvirus 68 Limits Naturally Occurring CD4+CD25+ T Regulatory Cell Activity following Infection

“…apparent that these cells can affect the host response following infection with pathogens (20 -22). Unfortunately, it is not always clear what role CD4 ϩ CD25 ϩ T regulatory cells might have during microbial infections because they may function to suppress the protective immune response (23,24,25), or because they may limit the destructive effects of pathogen-induced inflammation (17). Therefore, we undertook these studies to determine what role naturally occurring CD4 ϩ CD25 ϩ T regulatory cells might have during infection with a ␥-herpesvirus, ␥HV-68.…”

“…ϩ T lymphocyte activity (24), or contributing to viral-induced disease progression (25). However, increases in CD4 ϩ CD25 ϩ T regulatory cell activity following some viral infections serve to limit the destructive nature of pathogen-induced inflammation.…”

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

“…Regulatory T cells (CD4 + CD25 + ) are a crucial component for the control of deleterious effects from excessive immune responses as seen in autoimmune disease or allergic insult [1,2]. Treg cells have been implicated in a number of pathologic processes including elevated levels in cancers [3][4][5] and infectious diseases [6][7][8][9], and reduced levels in autoimmune diseases [1,[10][11][12][13]. It is apparent that Treg cells are induced (or recruited and expanded) by most infections to modulate host immune responses to avoid overreactive immunity (Fig.…”