Biased Generation and In Situ Activation of Lung Tissue–Resident Memory CD4 T Cells in the Pathogenesis of Allergic Asthma

Abstract

Asthma is a chronic inflammatory disease mediated by allergen-specific CD4 T cells that promote lung inflammation through recruitment of cellular effectors into the lung. A subset of lung T cells can persist as tissue-resident memory T cells (TRMs) following infection and allergen induction, although the generation and role of TRM in asthma persistence and pathogenesis remain unclear. In this study, we used a mouse model of chronic exposure to intranasal house dust mite (HDM) extract to dissect how lung TRMs are generated and function in the persistence and pathogenesis of allergic airway disease. We demonstrate that both CD4 and CD8 T cells infiltrate into the lung tissue during acute HDM exposure; however, only CD4 TRMs, and not CD8 TRMs, persist long term following cessation of HDM administration. Lung CD4 TRMs are localized around airways and are rapidly reactivated upon allergen re-exposure accompanied by the rapid induction of airway hyperresponsiveness independent of circulating T cells. Lung CD4 TRM activation to HDM challenge is also accompanied by increased recruitment and activation of dendritic cells in the lungs. Our results indicate that lung CD4 TRMs can perpetuate allergen-specific sensitization and direct early inflammatory signals that promote rapid lung pathology, suggesting that targeting lung CD4 TRMs could have therapeutic benefit in alleviating recurrent asthma episodes.

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…180,181 In response to prolonged allergen exposure, a similar CD69 + and Th2-biased CD4 + T RM population persists in the lung parenchyma. 182 Even in the absence of circulating T cells, these CD4 + T RM s are sufficient to mount a robust recall response. Similar autologous recall response has also been observed for helminth-induced lung CD4 + T RM s after T cell migration has been blocked.…”

Origins of CD4+ circulating and tissue‐resident memory T‐cells

“…These results suggest a possible antagonistic relationship between T RM and memory T FH cells, and highlight a role for TFs in directing the development of tissue‐resident populations. In another study using the HDM model, lung CD4 + T RM clustered around the airways at rest and rapidly reactivated upon secondary exposure within their clusters to produce IL‐4, IL‐5 and IL‐17 and recruit dendritic cells . Additional studies highlight a role for IL‐7, along with IL‐2, in the maintenance of allergen‐specific CD4 + T RM cells in the lung parenchyma and airways.…”

“…In another study using the HDM model, lung CD4 + T RM clustered around the airways at rest and rapidly reactivated upon secondary exposure within their clusters to produce IL-4, IL-5 and IL-17 and recruit dendritic cells. 50 Additional studies highlight a role for IL-7, along with IL-2, in the maintenance of allergen-specific CD4 + T RM cells in the lung parenchyma and airways. However, these IL-7-dependent CD4 + T RM did not express CD69, 52 suggesting either that CD69 may not be a conclusive marker for CD4 + T RM or that CD4 + T RM are highly heterogeneous, and further studies must focus on elucidating the different subsets.…”

“…This may be an optimized way for helper T RM cells to perform their ‘sense‐and‐alarm’ function, initiating the innate response to recruit circulating cells and activating CD8 + T‐cells to fight off pathogen. Additionally, cytokines appear to be critical in the recruitment, formation and maintenance of CD4 + T RM in many tissues . However, which cytokines are important for which tissues remain unknown, although IL‐2 may play a key role for all T RM given its known effects in circulating memory populations .…”

“…Much like circulating CD4 + memory T-cells, studies of tissue-resident lymphocytes have predominantly focused on CD8 + T RM due to the heterogeneity of CD4 + memory T-cells and the existing gaps in knowledge regarding mechanisms governing memory CD4 + T-cell formation. Nevertheless, recent studies have highlighted a prominent population of long-lived CD4 + T-cells within many nonlymphoid tissues, including the lungs, 36,[49][50][51][52][53][54][55][56][57] small intestine (SI), 12,18,[58][59][60] skin, 15,[61][62][63][64] and female reproductive tract (FRT) 18,65,66 (Fig. 2).…”