Environmental and Antigen Receptor-Derived Signals Support Sustained Surveillance of the Lungs by Pathogen-Specific Cytotoxic T Lymphocytes

Abstract

Viral infections often gain access to the body of their host by exploiting areas of natural vulnerability, such as the semipermeable surfaces of mucosal tissues which are adapted for adsorption of nutrients and other diffusible molecules. Once the microbes have crossed the epithelial barrier, they can disperse to other tissues where eradication may not be possible. The best opportunity for successful immune intervention is immediately after infection while the pathogen is confined to a localized area of the body. Cytotoxic T lymphocytes (CTL) which reside at the site where the infection begins can make an important contribution to immunity by reducing early dissemination of the infection. Because the lungs provide easy access points for many pathogens to enter the body, they require protection from many complementary mechanisms, including pathogen-specific cytotoxic T cells. In this study we show that an enduring response to pathogen-derived peptide antigens facilitates sustained surveillance of the lungs by pathogen-specific CTL during the recovery from influenza virus infection. Our studies show that these processed peptide antigens reinforce expression of two homing receptors (CD69 and CD103) which help recently activated virus-specific CTL colonize the lungs during a mild inflammatory response. We suggest that this requirement for prolonged antigen presentation to reinforce local CTL responses in the lungs explains why protective cellular immunity quickly declines following influenza virus infection and other viral infections that enter the body via mucosal tissues.

Cutting Edge: CD69 Interference with Sphingosine-1-Phosphate Receptor Function Regulates Peripheral T Cell Retention

“…Interestingly, Ag recognition and exposure to type I IFN do not appear to be strictly required for CD69 induction in T cells, consistent with the observation that T RM cells can form in the absence of local Ag recognition or overt inflammation (3,(5)(6)(7). Nevertheless, given the strong induction of CD69 expression by Ag stimulation and exposure to inflammatory cytokines, it appears likely that such signals cooperate to support effector T cell retention and T RM cell generation (2,6,12,19). Overall, our results define the early induction of CD69 expression as an important checkpoint in peripheral effector T cell retention and the generation of long-lived immune memory at body surfaces.…”

“…As a consequence, CD69 induction can block S1P-mediated T cell egress from lymphoid tissues (17). Despite this, following virus infection, peak numbers of circulating Cd69 2/2 effector CD8 T cells appear normal (3,18,19). Although such results indicate that CD69-dependent regulation of S1P 1 -mediated egress from lymph nodes (LNs) may have surprisingly little impact on the expansion of virus-specific CD8 T cells, we showed recently that CD69 expression is required for optimal T RM cell formation in nonlymphoid tissues, such as skin and dorsal root ganglia, following infection with HSV (3).…”

Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation

“…Thus, the ability to support efficient T RM lodgement by local inflammation and their long-term persistence in the absence of ongoing antigen-presentation expands the potential use of this population in infection control. It means that T RM cells can be used to protect the epithelial surfaces that form key pathogen entry points in the body without the use of vectors that drive ongoing presentation, as is otherwise necessary for effective peripheral immunity based on circulating memory T cells (9,34,42).…”

Aging impacts CD103+CD8+ T cell presence and induction by dendritic cells in the genital tract

“…From a mechanistic standpoint, others have shown that TGFβ production in certain tissues promotes CD103 expression, either soluble TGFβ or membrane‐bound TGFβ (Casey et al., 2012; Lee et al., 2011; Mackay et al., 2013; Yu et al., 2013). Our studies build on this foundation to demonstrate that signaling through TGFβ bound to the membrane of endometrial DCs was responsible for the induction of CD103 on naïve CD8 + T cells.…”