NK1.1+ innate lymphoid cells in salivary glands inhibit establishment of tissue-resident memory CD8+ T cells in mice.

NK1.1+ cells found in salivary glands (SG) represent a unique cell population of innate lymphoid cells (ILC) with characteristics of both conventional NK cells and ILC1. Here, we demonstrate that these NK1.1+  cells limit the accumulation and differentiation of virus-specific tissue-resident memory CD8+ T cells (TRM  cells) in SG of mice infected with lymphocytic choriomeningitis virus (LCMV). The negative regulation of LCMV-specific CD8+ TRM  cells by NK1.1+  cells in SG is independent of NKG2D, NKp46, TRAIL, and perforin. Moreover, analysis of NKp46iCre+ Eomesfl/fl mice revealed that Eomes-dependent conventional NK cells are dispensable for negative regulation. Since the SG are prone to autoimmune reactions, regulation of TRM  cells by tissue-resident ILC may be particularly important to prevent immunopathology in this organ.

α4 ß1 integrin promotes accumulation of tissue-resident memory CD8+ T cells in salivary glands.

The salivary glands (SGs) of virus-immune mice contain substantial numbers of tissue-resident memory CD8+ T cells (TRM cells) that can provide immunity to local infections. Integrins regulate entry of activated T cells into nonlymphoid tissues but the molecules that mediate migration of virus-specific CD8+ T cells to the SGs have not yet been defined. Here, we found that polyinosinic-polycytidylic acid (poly(I:C)) strongly promoted the accumulation of P14 TCR-transgenic CD8+ TRM cells in SGs in an α4 ß1 integrin-dependent manner. After infection with lymphocytic choriomeningitis virus, accumulation of P14 TRM cells in SGs and intestine but not in kidney was also α4 integrin dependent. Blockade of α4 ß7 by monoclonal antibodies (mAbs) inhibited lymphocytic choriomeningitis virus-induced accumulation of P14 TRM cells in the intestine but not in SGs. In conclusion, our data reveal that α4 ß1 integrin mediates CD8+ TRM accumulation in SGs and that poly(I:C) can be used to direct activated CD8+ T cells to this organ.

TGF-ß downregulates KLRG1 expression in mouse and human CD8(+) T cells.

The inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) and the integrin αE (CD103) are expressed by CD8(+) T cells and both are specific for E-cadherin. However, KLRG1 ligation by E-cadherin inhibits effector T-cell function, whereas binding of CD103 to E-cadherin enhances cell-cell interaction and promotes target cell lysis. Here, we demonstrate that KLRG1 and CD103 expression in CD8(+) T cells from untreated and virus-infected mice are mutually exclusive. Inverse correlation of KLRG1 and CD103 expression was also found in human CD8(+) T cells-infiltrating hepatocellular carcinomas. As TGF-ß is known to induce CD103 expression in CD8(+) T cells, we examined whether this cytokine also regulates KLRG1 expression. Indeed, our data further reveal that TGF-ß signaling in mouse as well as in human CD8(+) T cells downregulates KLRG1 expression. This finding provides a rationale for the reciprocal expression of KLRG1 and CD103 in different CD8(+) T-cell subsets. In addition, it points to the limitation of KLRG1 as a marker for terminally differentiated CD8(+) T cells if lymphocytes from tissues expressing high levels of TGF-ß are analyzed.