Systemic inflammation drives rapid conversion of conventional CD4+ T cells to Treg in vivo

The immune system faces a task that approximates cognition in its complexity as it processes a multitude of intrinsic and extrinsic signals and integrates these into responses of the appropriate class, specificity, magnitude, and duration for a given threat, with the host's life often depending on the outcome. CD4+ T lymphocytes occupy a unique role in the generation and regulation of immunity within this context and influence multiple innate and adaptive cell types. With respect to CD8+ cytotoxic T lymphocytes (CTL), CD4+ T cells function early in the response as 'helpers' (TH) to increase its magnitude and functionality, and later as regulatory cells (Treg) to restore homeostasis and avoid immune pathology. Using a Listeria monocytogenes (Lm) infection model, we probed whether the conditions of initial pathogen encounter could influence the generation of TH versus Treg. At low dose infection, CD4+ T cells 'help' CTLs via CD40-CD40L signaling, while high dose infection induces rapid polyclonal conversion to functional FoxP3+CD25+ Treg within 24 hours. These findings resolve long-standing questions regarding the requirement for TH and reveal a remarkable degree of plasticity in the function of CD4+ T cells, which can be quickly converted to Treg in vivo in response to acute inflammation. Overall design: Differential gene expression analysis of total RNA isolated from splenic CD4+eGFP- (Tconv) and CD4+eGFP+ (Treg) from Foxp3eGFP mice following low dose and high dose Lm ?actA-Ova infections.