T cell-intrinsic PRR signaling in immunity and pathology

Abstract

The immune system orchestrates a delicate balance between robust defense against pathogens and restraint to prevent tissue damage, with T cells serving as central mediators of adaptive immunity. The canonical pathway for T-cell activation hinges on the precise recognition of peptide antigens presented by major histocompatibility complex (MHC) molecules via the T-cell receptor (TCR), which is complemented by essential co-stimulatory signals. However, this model alone cannot fully explain the nuanced contextualization of immune responses, particularly how T cells integrate signals related to the nature of the threat. Pattern recognition receptors (PRRs), which are traditionally studied in innate immune cells, are recognized as critical regulators of T cell function, challenging the conventional dichotomy between innate and adaptive immunity. T cell-intrinsic PRR signaling integrates endogenous danger signals and microbes to modulate critical processes, including cytokine production, proliferation, and polarization, thereby shaping immune responses and disease outcomes in contexts ranging from viral infections to chronic inflammation and cancer. However, the molecular mechanisms underlying PRR-mediated T cell regulation and their contributions to immune homeostasis or pathology remain incompletely understood. This study investigates the role of T cell-intrinsic PRR signaling in shaping immune responses and its implications for disease. By elucidating key signaling pathways and their impact on T cell function, we aim to offer novel insights into the complex regulation of T cell-mediated immunity and uncover an underappreciated paradigm for immune-related disorders, providing new insights into the pathogenesis of inflammatory and neoplastic diseases.

1. Introduction

Pattern recognition receptors (PRRs), a class of evolutionarily conserved biomolecules, are understood to be expressed across all cell types. However, their initial discovery and research focused on innate immunity, which is considered an important line of defense against infection [1,2]. The body’s initial perception of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) is mediated by PRRs, which include families such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs), and AIM2-like receptors (ALRs) [3–8].

Recently, accumulating evidence has revealed significant limitations in this traditional, innate-centric understanding of PRR biology [9–11]. First, the cellular distribution of PRRs has historically been underestimated. However, a long-standing dogma holds that PRR expression is largely confined to innate immune cells, such as macrophages, dendritic cells, and neutrophils [3–5]. Importantly, the advent of sophisticated high-throughput technologies has unequivocally demonstrated functional PRR expression within human and mouse T lymphocytes [12,13]. Consequently, the direct function of PRRs, particularly their intrinsic functions within T lymphocytes, has emerged as a major focus of contemporary research [14–16]. Despite this growing interest, our understanding of how PRRs directly influence T-cell development, differentiation, and effector functions remains remarkably limited, with fundamental mechanistic insights still lacking. Second, the downstream signalosomes of PRR engagement were oversimplified. The canonical view emphasized the activation of the NF-κB, MAPK, and interferon pathways, which primarily drive pro-inflammatory cytokine production [17,18]. However, recent discoveries highlight a far broader functional repertoire, revealing that PRRs are potent regulators of immunometabolism and influence diverse cellular processes beyond classical inflammation [12,14–16,19]. The full scope of biological activities governed by PRR signaling is still being actively explored. Third, the pathological implications of PRR signaling have often been viewed through an overly simplistic lens. Although essential for host defense, PRR activation is not invariably beneficial. Emerging data underscore its dual effects: dysregulated signaling through specific PRRs is increasingly implicated in the pathogenesis of autoimmune diseases, whereas in other contexts, such as chronic infections or cancer, aberrant PRR activity can paradoxically impair protective immunity or promote immune evasion [20–22]. Finally, the fundamental immunological principles governing PRR actions, particularly within adaptive immune cells such as T cells, remain incompletely defined. A deeper understanding of the core rules dictating context-dependent outcomes, signal integration with