The Regulation of Inflammation by Innate and Adaptive Lymphocytes

Abstract

Inflammation plays an essential role in the control of pathogens and in shaping the ensuing adaptive immune responses. Traditionally, innate immunity has been described as a rapid response triggered through generic and nonspecific means that by definition lacks the ability to remember. Recently, it has become clear that some innate immune cells are epigenetically reprogrammed or "imprinted" by past experiences. These "trained" innate immune cells display altered inflammatory responses upon subsequent pathogen encounter. Remembrance of past pathogen encounters has classically been attributed to cohorts of antigen-specific memory T and B cells following the resolution of infection. During recall responses, memory T and B cells quickly respond by proliferating, producing effector cytokines, and performing various effector functions. An often-overlooked effector function of memory CD4 and CD8 T cells is the promotion of an inflammatory milieu at the initial site of infection that mirrors the primary encounter. This memory-conditioned inflammatory response, in conjunction with other secondary effector T cell functions, results in better control and more rapid resolution of both infection and the associated tissue pathology. Recent advancements in our understanding of inflammatory triggers, imprinting of the innate immune responses, and the role of T cell memory in regulating inflammation are discussed.

Figure 1

Memory T cells regulate inflammation at sites of infection. Traditional paradigms of innate instruction of adaptive immunity must now also appreciate that adaptive memory T cells regulate both the nature and shape of innate inflammatory responses. Memory CD4 T cell-mediated enhanced inflammatory responses are initiated independently of the classic PRR signaling and classic costimulatory molecule recognition and are better at containing virus than innate responses triggered in naïve hosts through PAMP-dependent mechanisms.

Figure 2

Memory T cells regulate the accumulation and functional potential of secondary effector T cells in the lung through antigen-specific upregulation of the inflammatory cytokine IL-6. Following secondary IAV infection, the earlier and more robust inflammatory response induced by memory CD4 T cells correlates with improved control of the virus in the lung. One innate inflammatory cytokine involved in this response, IL-6, plays a central role in maximizing the multicytokine-producing potential of secondary CD4⁺ T effector cells that accumulate in the lung at the peak of the recall response. Experienced memory cells thus modulate the effector functions of recently expanded secondary effector T cells that arise from resting memory T cell precursors during recall responses by inducing potent inflammatory signals.