CD4+CD25+ T Cells Regulate Virus-specific Primary and Memory CD8+ T Cell Responses

Abstract

Naturally occurring CD4+CD25+ regulatory T cells appear important to prevent activation of autoreactive T cells. This article demonstrates that the magnitude of a CD8+ T cell–mediated immune response to an acute viral infection is also subject to control by CD4+CD25+ T regulatory cells (Treg). Accordingly, if natural Treg were depleted with specific anti-CD25 antibody before infection with HSV, the resultant CD8+ T cell response to the immunodominant peptide SSIEFARL was significantly enhanced. This was shown by several in vitro measures of CD8+ T cell reactivity and by assays that directly determine CD8+ T cell function, such as proliferation and cytotoxicity in vivo. The enhanced responsiveness in CD25-depleted animals was between three- and fourfold with the effect evident both in the acute and memory phases of the immune response. Surprisingly, HSV infection resulted in enhanced Treg function with such cells able to suppress CD8+ T cell responses to both viral and unrelated antigens. Our results are discussed both in term of how viral infection might temporarily diminish immunity to other infectious agents and their application to vaccines. Thus, controlling suppressor effects at the time of vaccination could result in more effective immunity.

Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection

“…To determine whether it was possible to restore IFN-␥ production by HCV-specific CD4ϩ T cells in vitro, the effect of IL-2 addition was studied. In addition, CD25ϩ regulatory CD4ϩ T cells have been shown to play important roles in the control of a variety of responses against pathogens in both human and animal models, [28][29][30][31][32] and a role for such activity in control of HCV-specific CD8ϩ T cell responses has been proposed. 33 CD25ϩ T cells may compete for IL-2, thus effectively lowering the concentration available for antigenspecific T cells.…”

Association ofCTLA4 polymorphism with regulatory T cell frequency

“…Characterized phenotypically by constitutive expression of IL-2Ra (CD25), these cells were first identified by their role in maintaining self tolerance. Subsequently, CD4 + CD25 + T cells (Treg) have also been shown to play a central role in restraining the vigor of immune responses to pathogens [8][9][10][11][12][13][14][15]. While CTLA-4 was classically thought to restrain T cell responses by acting in cis on activated T cells [1], it has become clear that CTLA-4 can also act in trans [16,17].…”

Steady State Dendritic Cells Present Parenchymal Self-Antigen and Contribute to, but Are Not Essential for, Tolerization of Naive and Th1 Effector CD4 Cells

“…In vivo neutralization of CD4 ϩ CD25 ϩ Tregs was performed using the anti-CD25 mAb PC61 (eBioscience) as previously described (28,(33)(34)(35). In short, adoptive transfer recipients were treated i.v.…”

“…To test this possibility, Treg function was neutralized using the established protocol of treatment with the anti-CD25 mAb PC61 (33)(34)(35)38). Naive clonotypic CD4 cells were adoptively transferred into C3-HA low and viral-HA (control) recipients that had been treated with either PC61 or rat Ig (control) 4 days earlier, and were recovered from spleens 5 days posttransfer for analysis.…”