Regulatory CD4+CD25+ T Cells Restrict Memory CD8+ T Cell Responses

Abstract

CD4+ T cell help is important for the generation of CD8+ T cell responses. We used depleting anti-CD4 mAb to analyze the role of CD4+ T cells for memory CD8+ T cell responses after secondary infection of mice with the intracellular bacterium Listeria monocytogenes, or after boost immunization by specific peptide or DNA vaccination. Surprisingly, anti-CD4 mAb treatment during secondary CD8+ T cell responses markedly enlarged the population size of antigen-specific CD8+ T cells. After boost immunization with peptide or DNA, this effect was particularly profound, and antigen-specific CD8+ T cell populations were enlarged at least 10-fold. In terms of cytokine production and cytotoxicity, the enlarged CD8+ T cell population consisted of functional effector T cells. In depletion and transfer experiments, the suppressive function could be ascribed to CD4+CD25+ T cells. Our results demonstrate that CD4+ T cells control the CD8+ T cell response in two directions. Initially, they promote the generation of a CD8+ T cell responses and later they restrain the strength of the CD8+ T cell memory response. Down-modulation of CD8+ T cell responses during infection could prevent harmful consequences after eradication of the pathogen.

Differences in maintenance of CD8+ and CD4+ bacteria‐specific effector‐memory T cell populations

“…Three observations in the bacterial infection model support this hypothesis: (1) Despite decreasing numbers of bacteria-specific CD4 + memory T cells, the quality of protective immunity is not negatively affected; even after complete depletion of CD4 + T cells following primary infection, CD8 + Listeria-specific memory T cells are maintained and mediate effective protective immunity [32]. Interestingly, depletion of CD4 + T cells actually enhances the CD8 + memory T cell response [33]. (2) Upon antigen encounter, CD4 + recall effector T cells have the potential to rapidly re-expand out of the small memory T cell populations.…”

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].…”

Innate and adaptive immune responses to Listeria monocytogenes: a short overview

“…Important for preventing autoimmunity, during infection regulatory T cells play a role in down-regulating the T cell responses. No role has been shown for these cells during primary L. monocytogenes infection, but during a rechallenge response CD4 + CD25 + cells are important for limiting the expansion of memory CD8 T cells [75].…”