Antigen-Independent Differentiation and Maintenance of Effector-like Resident Memory T Cells in Tissues

Abstract

Differentiation and maintenance of recirculating effector memory CD8 T cells (TEM) depends on prolonged cognate antigen stimulation. Whether similar pathways of differentiation exist for recently identified tissue-resident effector memory T cells (TRM), which contribute to rapid local protection upon pathogen re-exposure, is unknown. Memory CD8αβ+ T cells within small intestine epithelium are well-characterized examples of TRM and they maintain a long-lived effector-like phenotype that is highly suggestive of persistent antigen stimulation. This study sought to define the sources and requirements for prolonged Ag-stimulation in programming this differentiation state, including local stimulation via cognate or cross-reactive antigens derived from pathogens, microbial flora, or dietary proteins. Contrary to expectations, we found that prolonged cognate Ag-stimulation was dispensable for intestinal TRM ontogeny. In fact, chronic antigenic stimulation skewed differentiation away from the canonical intestinal T cell phenotype. Resident memory signatures, CD69 and CD103, were expressed in many non-lymphoid tissues including intestine, stomach, kidney, reproductive tract, pancreas, brain, heart, and salivary gland, and could be driven by cytokines. Moreover, TGFβ driven CD103 expression was required for TRM maintenance within intestinal epithelium in vivo. Thus, induction and maintenance of long-lived effector-like intestinal TRM differed from classic models of TEM ontogeny, and were programmed through a novel location-dependent pathway that was required for the persistence of local immunological memory.

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

“…DCs can provide Ag and type I IFN for CD69 induction in T cells in vitro TCR-dependent activation and exposure to various combinations of cytokines, including type I IFN, IL-33, TNF-a, and TGF-b, induce CD69 expression in T cells (7,22). Given that we observed CD69 expression by T cells in both skin epithelium and dermis, we contemplated whether DCs accumulating in these tissue compartments during infection (21) could provide the relevant Ag and/or noncognate activation signals to T cells.…”

“…These T RM cells provide immediate local immunity (2,5,6) and, therefore, their generation holds promise for novel vaccines against pathogens that target barrier tissues, such as skin and mucosa. Although some aspects of peripheral memory formation were determined recently, such as the contributions of the cytokines TGF-b and IL-15 (3,4,7), the molecular mechanisms regulating early effector T cell retention as a prerequisite for subsequent T RM cell differentiation are not fully understood.…”

Immunological memories of the bone marrow

“…CD103 mediates binding to E‐cadherin, which is expressed on epithelial cells 161. Mice lacking CD103 show defects in establishing antigen‐experienced “tissue‐resident” T cells of peripheral tissues 162. For the establishment of bone marrow‐resident memory CD4 lymphocytes, we have shown that CD69 is essential 137.…”

“…Antigen is needed for the differentiation of T cells into “tissue‐resident” T cells 157, 166. They seem to play a prominent role in controlling persistent, latent infections,167 but apparently can also be maintained in the absence of antigen 162. “Tissue‐resident” memory T cells have been postulated to survive in dedicated niches providing them with distinct survival signals, such as CD103/E‐Cadherin166 or CD49a/Collagen type I and IV 168.…”

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.…”