E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands

Abstract

The salivary glands are important effector sites for IgA-mediated humoral immunity to protect oral surfaces. Within murine submandibular glands (SMG), we identified a memory CD8 T-cell population that exhibited a unique cell-surface phenotype distinct from memory CD8 T cells in spleen but similar to memory T cells resident in the intraepithelial lymphocyte compartment of the intestinal mucosa. In mice immune to lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), virus-specific memory CD8 T cells with this unusual phenotype were present in SMG at remarkably high frequencies. LCMV-specific memory CD8 T cells in SMG showed potent functional activities in vivo, including cytokine-induced bystander proliferation, antigen-triggered IFNγ production, and viral clearance. Adoptive transfer experiments further revealed that the capacity to accumulate in SMG decreased during CD8 Tcell differentiation and that SMG CD8 T cells were poorly replenished from the circulation, indicating that they were tissue-resident. Moreover, they preferentially relocalized within their tissue of origin after adoptive transfer and antigen rechallenge, thus revealing an imprinted differentiation status. Accumulation of memory CD8 T cells within SMG did not require local antigen presentation but was promoted by the epithelial differentiation molecule E-cadherin intrinsically expressed by these CD8 T cells. This finding extends the epithelial-restricted function of E-cadherin to an impact on lymphocyte accumulation within epithelial tissues.epithelial tissues | viral infections T he establishment of a multilayered memory T-cell system provides high flexibility to combat reinfections with different pathogens. Central memory T cells (T CM ) build up a long-lasting pool of rapidly replicating cells in secondary lymphoid organs whereas effector memory T cells (T EM ) patrolling blood, spleen, and nonlymphoid tissues are crucial to fighting incoming infections by immediate effector functions (1, 2). Parabiosis experiments, however, revealed that entry of blood-borne memory T cells into brain and gut lamina propria is restricted (3). Moreover, recent studies have suggested a prominent role of tissueresident memory T cells (T RM ) in providing local protection (4). Virus-specific CD8 T RM cells have been described in sensory ganglia, skin, brain, and intestinal mucosa (4-11). Common features of differently localized T RM cells are the expressions of the α E β 7 integrin CD103 and of CD69 (4,5,7,9). Submandibular glands (SMG) are accessory organs of the oral mucosa and well-characterized effector sites of the mucosal IgA response (12, 13). In addition to B cells, SMG also accommodate αβ and γδ T cells, NK cells, and other innate immune cell populations (13, 14). The glandular tissue further represents an important target organ for cytomegalovirus infections and for autoimmune reactions (15, 16). As SMG are exocrine epithelial tissues, the epithelial differentiation molecule E-cadherin is highly expressed in these organs. E-cadh...

Tissue-Resident Memory T Cells and Fixed Immune Surveillance in Nonlymphoid Organs

“…Residency is far more widespread than previously envisaged, and its basis is inherent to the T RM cells rather than the tissue in which they lodge (27,36,37). CD8 + T RM cells are found throughout the body, with their detection reported in lung, kidney, brain, and salivary gland (29,(38)(39)(40). In addition, some memory cells in primary and secondary lymphoid organs remain fixed and fail to equilibrate with the wider circulation (41)(42)(43).…”

“…T RM cells lodged in peripheral tissues are broadly functional (40,76) and capable of protecting against infection (24,39,48,57). Indeed, in cases in which comparison between T RM cells and circulating memory cells was possible, T RM cell involvement proved pivotal in infection control (30,31,77).…”

“…CD103 is the a-chain of the integrin a E b 7 , which binds E-cadherin expressed on epithelial cells in skin and gut (27,39,(53)(54)(55). E-cadherin is also expressed by T RM cells in a range of organs (28,40).…”

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

“…CD103, part of the α E (CD103)β 7 integrin, is expressed by CD8 + T RM cells in different peripheral tissues (19,25,26), and has been shown to be important for survival of T cells in these compartments (26,27). Accordingly, T cells embedded in skin by DNFB treatment expressed high levels of CD103 (Fig.…”

Tissue Distribution of Memory T and B Cells in Rhesus Monkeys following Influenza A Infection

“…These long-lived nonrecirculating T RM cells permanently reside in nonlymphoid tissues including skin, brain, vagina, and lung and provide rapid, effective local protection against reinfection relative to circulating counterpart memory T cells (10,11). Local immune protection by T RM cells has been consistently documented in murine models of virus and bacterial infections including vaccinia virus, lymphocytic choriomeningitis virus, HSV, influenza, and tuberculosis (12)(13)(14)(15)(16). Recent studies have revealed delivery of vaccinia virus in mice via skin scarification generates long-lived skin T RM CD8 + T cells associated with improved long-term immunity (12,17).…”