T_RMIntegrins CD103 and CD49a Differentially Support Adherence and Motility After Resolution of Influenza Virus Infection

Abstract

Tissue resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon re-exposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1).Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by two-weeks postinfection and that each integrin contributes a distinct function regulating CD8 T cell motility both in vitro and in vivo, with CD49a facilitating migration and CD103 limiting motility through tethering. These results demonstrate for the first time how CD103 and CD49a differentially impact adherence and migration in the tissue, likely affecting overall retention, maintenance of TRM, and host protection. Significance Statement:Current influenza vaccination strategies require annual immunizations, with fairly low efficacy rates. One technique to improve protection against a greater breadth of influenza viruses is to elicit broadly cross-reactive cell-mediated immunity and generate a local population of cytotoxic T cells to respond to conserved regions of circulating viruses. However, this approach requires improved understanding of how these cells migrate within and attach to the tissue, in order to persist and offer long-term immunity. This study investigates how receptors on the T cell surface impact the cell's ability to interact with the tissue and provide evidence for which of these receptors are essential for protection. Furthermore, these studies reveal functional in vivo mechanisms of cellular markers used to characterize TRM. Introduction:

Formation and Maintenance of Tissue Resident Memory CD8+ T Cells after Viral Infection

“…Although CD69 is critical for T RM in some peripheral tissues (e.g., kidney), it does not appear to be a universal requirement for T RM in all sites [11]. Our lab has recently discovered that using CD49a and CD103 in combination identifies up to four potentially distinct memory T cell subsets in the lungs and airways (including trachea), although cells expressing only CD69 and CD103 do not appear to persist long-term [12]. Using all three markers may be necessary to paint the full picture of cell diversity, function, and gene expression profiles ( Table 1).…”

“…Virus-specific CD8 cells that express CD49a do not appear in the tissue until after the infection is cleared [4]. In influenza infection, CD8 T cells in the tissue express CD49a, CD69, and CD103 by day 14, suggesting cells with a T RM phenotype develop relatively early as the tissue recovers from infection [12]. There has been much speculation regarding when and where T RM cells form: Takamura demonstrated that in areas of repair after influenza infection, there are repair-associated memory depots (RAMD) containing populations of keratin-5+ cells that express alpha-V integrins [29].…”

Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis

“…Trm cells are a critical and unique component of the adaptive immune system, with specific roles in orchestrating downstream innate and adaptive responses upon reactivation [ 10 ]. They are most known for their roles in barrier function in mucosal tissue and the skin; however, they possess phenotypic variation between tissue types.…”

Tissue-resident memory CD8 T-cell responses elicited by a single injection of a multi-target COVID-19 vaccine

“…. CD103 and CD49a expression are key molecules in Trm biology since providing them the capacity of interaction, adherence and mobility with mucosal tissues, in particular epithelial cells and collagen directly underlying epithelial cells80,81 .To summarize, this differentiated Th1-biased memory CD8 T cell SARS-CoV-2 vaccine has been developed using reverse vaccinology selection approach, computational immunologyoptimization and synthetic peptide synthesis technology. The development of inactivated virus vaccine, besides Good Manufacturing Practices (GMP) system, require extremely high manufacture standard to avoid medical accidents due to the failure of complete inactivation of virus toxicity.…”