Santiago-Carvalho, Igor

Abstract Extracellular ATP (eATP) is a danger signal released by inflamed tissues, and can be sensed by immune cells via P2RX7. P2RX7 promotes lung pathology induced by influenza infection, by inducing exacerbated numbers of lung CD4+ T cells. In response to influenza, lung CD4+ T cells are comprised of a type 1 (Th1)-like population, and a subset resembling follicular helper (Tfh) CD4+ T cells; this subset is called tissue-resident helper (Trh). Trh cells amplify lung effector immune responses. Trh cells express high P2RX7 levels, and current research in our laboratory shows that P2RX7 is crucial for Trh cell establishment and subsequent lung damage. We have also found that the intensity of lung damage caused by influenza is positively correlated with P2RX7+ lung Trh cells. It is not clear, however, how concomitant exposure to influenza and type 2 immunity-inducing lung allergens (a common clinical occurrence in the United States) affect P2RX7+ lung Trh cells and their resultant tissue damage. We investigated this, using House Dust Mite (HDM) allergen exposure together with Influenza (PR8) infection. HDM/PR8 co-exposure induced worsening of lung inflammation, compared to single exposure to PR8. This inflammation had type 1 characteristics (i.e. parenchymal immune cell accumulation and absence of mucus). The increased lung damage generated by HDM/PR8 exacerbated the generation of influenza-specific P2RX7+ lung Trh cells. The accumulation of lung Trh cells (and subsequent tissue damage) caused by HDM/PR8 was abolished in T cell-specific P2RX7-knockout mice. Our results suggest that local inflammation, eATP release and sensing, and lung Trh cells together dictate the intensity of lung damage, regardless of the nature of the lung disease agent. R01AI170649

The activation and function of T cells is fundamental for the control of infectious diseases and cancer, and conversely can mediate several autoimmune diseases. Among the signaling pathways leading to T cell activation and function, the sensing of extracellular adenosine triphosphate (eATP) has been recently appreciated as an important component. Through a plethora of purinergic receptors, most prominently P2RX7, eATP sensing can induce a wide variety of processes in T cells, such as proliferation, subset differentiation, survival, or cell death. The downstream roles of eATP sensing can vary according to (a) the T cell subset, (b) the tissue where T cells are, and (c) the time after antigen exposure. In this mini-review, we revisit the recent findings on how eATP signaling pathways regulate T-cell immune responses and posit important unanswered questions on this field.