The potential of CD4 T-cell memory

Abstract

While many aspects of memory T-cell immunobiology have been characterized, we suggest that we know only a fraction of the effector functions that CD4 T cells can bring to bear during secondary challenges. Exploring the full impact of memory CD4 T-cell responses is key to the development of improved vaccines against many prominent pathogens, including influenza viruses, and also to a better understanding of the mechanisms of autoimmunity. Here we discuss factors regulating the generation of memory CD4 T cells during the activation of naïve cells and how the nature of the transition from highly activated effector to resting memory upon the resolution of primary responses might impact memory CD4 T-cell heterogeneity in vivo. We stress that memory CD4 T cells have unique functional attributes beyond the secretion of T helper (Th) subset-associated cytokines that can shape highly effective secondary responses through novel mechanisms. These include the recruitment of innate inflammatory responses at early phases of secondary responses as well as the action of enhanced direct effector functions at later phases, in addition to well-established helper roles for CD8 T-cell and B-cell responses.

Figure 1

Many factors can influence the generation of memory CD4 T cells. Variables present during T-cell activation, the effector phase, and after the resolution of a primary response can all impact the size and quality of the resulting memory population. APC, antigen-presenting cell; IL, interleukin; TCR, T-cell receptor.

Figure 2

Effector heterogeneity is influenced by several factors. While some effectors progress to a terminally differentiated state, the rapid kinetics of the effector-to-memory transition upon resolution of a primary immune response enables a great deal of heterogeneity to be retained in the memory phase. APC, antigen-presenting cell; TCR, T-cell receptor.

Figure 3

Memory CD4 T cells impact multiple stages of secondary responses. Memory CD4 T cells rapidly produce an array of cytokines and chemokines upon antigen recognition, and can recruit elements of the innate immune system to do likewise. As they divide and further differentiate, memory CD4 T cells can act as superior helpers for CD8 T-cell and B-cell responses compared with naïve CD4 T cells. Finally, highly activated secondary effectors impact secondary responses through direct effector functions that differ from those of primary effectors. All stages concertedly impact the kinetics of pathogen clearance.

Figure 4

Both through cell-to-cell contact and through cytokine and chemokine production, memory CD4 T cells have the potential to impact a broad range of both innate and adaptive immune functions during a secondary response. DC, dendritic cell.