Persistence of CD 4 T Cell Memory Negatively Regulates

Much is known about the differentiation of naive T cells into distinct lineages of effector cells, but the molecular mechanisms underlying the generation and maintenance of CD4 T cell memory are poorly characterized. Our studies ascribe a novel role for the cell cycle regulator p27 Kip1 as a prominent negative regulator of the establishment and long-term maintenance of Th1 CD4 T cell memory. We demonstrate that p27 Kip1 might restrict the differentiation and survival of memory precursors by increasing the T-bet/Bcl-6 ratio in effector CD4 T cells. By promoting apoptosis and contraction of effector CD4 T cells by mechanisms that are at least in part T cell intrinsic, p27 Kip1 markedly limits the abundance of memory CD4 T cells. Furthermore, we causally link p27 Kip1-dependent apoptosis to the decay of CD4 T cell memory, possibly by repressing the expression of g-chain receptors and the downstream effector of the Wnt/b-catenin signaling pathway, Tcf-1. We extend these findings by showing that the antagonistic effects of p27 Kip1 on CD4 T cell memory require its cyclin-dependent kinase-binding domain. Collectively, these findings provide key insights into the mechanisms underlying the governance of peripheral CD4 T cell homeostasis and identify p27 Kip1 as a target to enhance vaccine-induced CD4 T cell memory. C D4 T cells play a central role in orchestrating several facets of the anti-microbial immune response including macrophage-mediated defense, Ab production by B cells, activation and expansion of CD8 T cells, programming of CD8 T cell memory and maintenance of CD8 T cell responses during chronic viral infections (1, 2). In response to TCR and costimu-latory signals, CD4 T cells clonally expand and differentiate into distinct effector cell types, including Th1, Th2, Th9, Th17, and T follicular helper (T FH) cells, depending on the type of infection and lineage-specifying signals delivered to the responding T cells early in the infection (3). Typically, acute viral and intracellular bacterial infections stimulate a Th1 and T FH effector response (4, 5). Following clearance of the pathogen, most effector CD4 T cells are lost, but a fraction of these cells that are programmed to survive differentiate into memory cells, which subsequently decline with an estimated half-life of 50–100 d (4–7). However, the mechanisms that control the differentiation or the attrition of memory CD4 T cells are not well understood. Understanding the differentiation of effector and memory CD4 T cells is a highly active area of investigation. …