Development and Function of Protective and Pathologic Memory CD4 T Cells

Abstract

Immunological memory is one of the defining features of the adaptive immune system. As key orchestrators and mediators of immunity, CD4 T cells are central to the vast majority of adaptive immune responses. Generated following an immune response, memory CD4 T cells retain pertinent information about their activation environment enabling them to make rapid effector responses upon reactivation. These responses can either benefit the host by hastening the control of pathogens or cause damaging immunopathology. Here, we will discuss the diversity of the memory CD4 T cell pool, the signals that influence the transition of activated T cells into that pool, and highlight how activation requirements differ between naïve and memory CD4 T cells. A greater understanding of these factors has the potential to aid the design of more effective vaccines and to improve regulation of pathologic CD4 T cells, such as in the context of autoimmunity and allergy.

Keywords: CD4 T cell; autoimmunity; cytokine; differentiation; epigenetic; infection; memory; vaccine.

Figure 1

Heterogeneity in memory CD4 T cells. Memory CD4 T cells can be found in lymphoid organs, blood, and at tissue sites. Stem cell memory T cells (Tscm) and central memory T (Tcm) cells are found in lymphoid organs and in the blood. Both populations are relatively undifferentiated compared to other memory CD4 T cell subsets, and are long lived. Follicular helper memory T (Tfh) cells can also be found in the blood and lymphoid organs. They express the B cell follicle homing receptor, CXCR5, which can position them near B cell follicles to provide rapid B cell help upon reactivation. Effector memory (Tem) and tissue resident memory T (Trm) cells can both be found in peripheral tissues and are more differentiated than Tcm and Tscm. Tem are migratory, passing through tissues and the blood, while Trm are restricted to tissues. Both populations can respond rapidly to tissue invading pathogens (, , –27).

Figure 2

Intrinsic changes in memory CD4 T cells which enhance their response to activation. There are a number of factors that can contribute to the distinct responses of memory CD4 T cells as compared to their naïve counterparts. T cell receptor (TCR) triggering can be enhanced in two ways: in polyclonal populations, the cells with the highest affinity for the antigen can come to dominate the response (1) alternatively, or in addition, the CD3 TCR-signaling complex is clustered more effectively in memory than naïve CD4 T cells (2). Intracellular signaling molecules are also altered: memory CD4 T cells contain more Zap 70 than naïve T cells (3) and TCR activation leads to increased phosphorylation of the MAPK, p38 (4). Changes in cell surface proteins, such as chemokine receptors (5) and integrins (6), affect cell migration and location enabling memory CD4 T cells to migrate rapidly to inflamed sites or reside permanently in pathogen-targeted tissues. Changes in gene transcription before and following T cell reactivation are also evident. Epigenetic differences between naïve and memory CD4 T cells enable more rapid transcription of effector molecules, such as cytokines, thereby accelerating the control and clearance of pathogens (, –101).