The inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) and the integrin α E (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-β 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-β 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-β are analyzed. Keywords:Killer cell lectin-like receptor G1 r α E (CD103) r E-cadherin. CD8 + T cell r TGF-β Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe killer cell lectin-like receptor G1 (KLRG1) is an E-cadherinspecific inhibitory receptor, which is expressed on different lymphocyte subsets [1][2][3][4]. It is frequently used as a marker for CD8 + T-cell differentiation and in combination with CD127 short-lived effector cells and memory precursor effector cells are discriminated [5]. KLRG1 is expressed in a substantial portion of effector and effector memory CD8 + T cells in blood and secondary lymphoid organs [6]. However, tissue-resident memory CD8 + T (T RM ) cells from various organs such as skin [7], small intestine [8], or Correspondence: Prof. Hanspeter Pircher e-mail: hanspeter.pircher@uniklinik-freiburg.de salivary glands (SG) [9] do not express KLRG1. Similarly, effector memory CD8 + T cells from tumor-infiltrated lymph nodes and tumor tissue show decreased KLRG1 expression compared to cells from the periphery [10,11]. The integrin α E (CD103) represents another receptor for E-cadherin, which is also expressed on subsets of CD8 + T cells [12,13]. In contrast to KLRG1, which inhibits effector cell function [2,4], binding of CD103 to E-cadherin promotes target cell interaction and destruction by cytotoxic CD8 + T cells [14,15]. Thus, KLRG1 and CD103 influence the interaction of CD8 + T cells with their target cells in an opposite manner although they share the same ligand. Here, we demonstrate that KLRG1 and CD103 were reciprocally expressed in mouse as well as in human CD8 + T cells. As TGF-β is known to induce CD103 in CD8 + T cells [13], we further examined whether this cytokine also regulates KLRG1 expression in these cells. Results and discussion Reciprocal expression of KLRG1 and CD103 in mo...

The salivary glands (SGs) of virus-immune mice contain substantial numbers of tissue-resident memory CD8 T cells (T 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 T cells in SGs in an α β integrin-dependent manner. After infection with lymphocytic choriomeningitis virus, accumulation of P14 T cells in SGs and intestine but not in kidney was also α integrin dependent. Blockade of α β by monoclonal antibodies (mAbs) inhibited lymphocytic choriomeningitis virus-induced accumulation of P14 T cells in the intestine but not in SGs. In conclusion, our data reveal that α β integrin mediates CD8 T accumulation in SGs and that poly(I:C) can be used to direct activated CD8 T cells to this organ.

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 (T RM cells) in SG of mice infected with lymphocytic choriomeningitis virus (LCMV). The negative regulation of LCMV-specific CD8 + T RM cells by NK1.1 + cells in SG is independent of NKG2D, NKp46, TRAIL, and perforin. Moreover, analysis of NKp46 iCre+ Eomes fl/fl mice revealed that Eomes-dependent conventional NK cells are dispensable for negative regulation. Since the SG are prone to autoimmune reactions, regulation of T RM cells by tissue-resident ILC may be particularly important to prevent immunopathology in this organ.