Control of innate immunity by memory CD4 T cells

Abstract

How memory CD4 T cells contribute to protection upon pathogen -challenge is not fully understood. Beyond traditional helper functions for CD8 T cell and B cell responses, memory CD4 T cells can have a potent impact on the character and a magnitude of inflammatory responses. Here we discuss how memory CD4 T cell control of innate immunity at early time points after pathogen encounters can influence protective responses. We also discuss important aspects of the mechanism whereby memory CD4 T cells directly and indirectly impact the activation status of antigen-presenting cells and production of inflammatory cytokines and chemokines from multiple cell types. We suggest that control of innate immune responses by the adaptive immune system is a powerful protective mechanism associated with the memory state and represents an important fail-safe in the face of pathogens that fail to trigger robust inflammatory responses through conserved pattern recognition receptors.

Figure 1

Innate control of adaptive immunity. Uptake of pathogens or pathogen products by APC stimulates PAMP receptors (PAMPr) resulting in the upregulation of costimulatory molecules (COS) by APC as well as the production of innate inflammatory cytokines and chemokines (IIC). In addition to recognizing specific antigen presented by APC, COS and IIC are critical in driving naïve CD4 T cells to become properly polarized effector cells.

Figure 2

Memory CD4 T cell control of innate inflammation during influenza infection. Memory CD4 T cells recognizing influenza (flu) presented by APC drive upregulation of COS and IIC independently of PAMP signals. IIC produced by the initial interaction between memory CD4 T cells and APC call in diverse elements of the innate immune system into the infected lung that also produce IIC. IIC and perhaps other aspects of the enhanced innate response mediated by memory CD4 T cells act on lung epithelial cells to drive further IIC production and to control virus during the initial days of infection.

Figure 3

Memory CD4 T cell control of innate immunity. Recognition of PAMPs and DAMPs (A) is a crucial trigger initiating innate immune responses in the naïve state. In a primed environment, in addition to pattern recognition receptors, antigen-specific memory CD4 T cells can initiate inflammatory responses and APC activation even in the absence of PAMP/DAMP recognition (B).