Immunity to Respiratory Infection Is Reinforced Through Early Proliferation of Lymphoid TRM Cells and Prompt Arrival of Effector CD8 T Cells in the Lungs

Abstract

Cross-protection between serologically distinct strains of influenza A virus (IAV) is mediated by memory CD8 T cells that recognize epitopes from conserved viral proteins. Early viral control begins with activation of tissue-resident memory CD8 T cells (T RM ) cells at the site of viral replication. These CD8 T cells do not act in isolation, as protection against disseminated infection is reinforced by multiple waves of effector cells (T EFF ) that enter the lungs with different kinetics. To define how a protective CTL response evolves, we compared the functional properties of antiviral CD8 T cells in the respiratory tract and local lymphoid tissues. When analyzed 30 dpi, large numbers of antiviral CD8 T cells in the lungs and mediastinal lymph nodes (MLNs) expressed canonical markers of T RM cells (CD69 and/or CD103). The check point inhibitor PD-1 was also highly expressed on NP-specific CD8 T cells in the lungs, while the ratios of CD8 T cells expressing CD69 and CD103 varied according to antigen specificity. We next used in vitro experiments to identify conditions that induce a canonical T RM phenotype and found that that naïve and newly activated CD8 T cells maintain CD103 expression during culture with transforming growth factor-beta (TGFβ), while central memory CD8 T cells (T CM ) do not express CD103 under similar conditions. In vivo experiments showed that the distribution of antiviral CTLs in the MLN changed when immune mice were treated with reagents that block interactions with PD-L1. Importantly, the lymphoid T RM cells were poised for early proliferation upon reinfection with a different strain of IAV and defenses in the lungs were augmented by a transient increase in numbers of T EFF cells at the site of infection. As the interval between infections increased, lymphoid T RM cells were replaced with T CM cells which proliferated with delayed kinetics and contributed to an exaggerated inflammatory response in the lungs.

Circulating memory CD8+ T cells are limited in forming CD103+ tissue‐resident memory T cells at mucosal sites after reinfection

“…We found that circulating memory CD8 + T cells exhibit restricted chromatin accessibility at the Itgae locus, as compared to T N cells. Concordantly, T N cells but not T CM cells readily upregulated CD103 in response to TGF-β signaling, which has been previously observed in other infection models [21,50]. Hence, epigenetic imprinting at the Itgae locus may obstruct circulating memory CD8 + T cells from forming CD103 + T RM cells after reinfection.…”

Protective function and durability of mouse lymph node-resident memory CD8+ T cells

“…Consistent with a recent study, we show that primary IAV infection generates Trm cells within the lung-draining mLN and that these cells mirror the cell surface marker expression and residence of Trm cells within the lung ( Suarez-Ramirez et al, 2019 ; Stolley et al, 2020 ). Importantly, we find that repeated IAV encounters impart numerous changes in the transcriptional and functional landscape of LN Trm cell populations, including enhanced ability to defend the lymph node against viral infection.…”

Tissue‐resident innate immunity in the lung

“…[2][3][4] In addition, recent work suggests that tissue-resident B cells also form an important part of the adaptive immune defence in the lung. Many studies have focused on tissue-resident T cells (Trm cells) within lung tissues, and these adaptive immune cells have been shown to play an important part in host defence against a variety of pulmonary infections.…”

“…Many studies have focused on tissue-resident T cells (Trm cells) within lung tissues, and these adaptive immune cells have been shown to play an important part in host defence against a variety of pulmonary infections. [2][3][4] In addition, recent work suggests that tissue-resident B cells also form an important part of the adaptive immune defence in the lung. 5 However, it is important to remember that innate immune cells can also be tissue-resident and are vital in providing the first line of defence against inhaled allergens and pathogens.…”