Regulation of immune homeostasis by CD101

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Dysregulated interactions between microbial, genetic, geographic and habitual factors can result in an inadequate expression or function of individual molecules of the innate or adaptive immune system and can cause immune-mediated diseases or increase the susceptibility to infection. However, the molecules, which modulate the interactions of the infectious agents with the immune system of the patient and the mechanisms restricting the inflammatory processes to invasive tissue damage have been rarely characterized. We have identified CD101, a negative costimulatory molecule, preferentially expressed by immune cells within the gastro-intestinal tract, as critical regulator of peripheral immune homeostasis in three different disease models including experimental enterocolitis. The knockout of CD101 or allelic variations within the cd101 gene resulting in a reduced expression of CD101 enhanced the severity of immune-mediated disease and was associated with an impaired regulatory T cell function and augmented interleukin-17 responses. In addition, the expression of CD101 correlated inversely with the activity and severity of disease in patients with inflammatory bowel disease. As CD101 propagated the release of interleukin-10 by myeloid cells and CD101-expressing myeloid cells contributed to the control of bacterial replication and translocation, we hypothesize that CD101 exerts anti-inflammatory and anti-microbial effects in order to maintain peripheral immune tolerance. Thus, the overall goal of the present proposal is to determine the role of CD101 in directing cell-specific immune protection against inflammation and/or infection. Furthermore, our preliminary data suggest that hypoxia promotes CD101-expression, while some classes of bacteria suppress its expression and accumulate in CD101-/- animals and CD101-deficient cells under physiologic atmospheric oxygen conditions. Therefore we also propose that the induction of immunoregulatory processes is disrupted by pathobionts due to the suppression of CD101 expression. Thus, to dissect the mutual interplay of CD101, bacteria and complex oxygen gradients as observed, for example, in the physiologic environment of the gut or during inflammation, we aim to characterize a) the cell populations and signaling and metabolic pathways primarily and secondarily engaged by CD101, b) the functional consequences of a cell-specific CD101 deletion and c) the factors which regulate the expression of CD101.Based on the currently available data CD101 appears to suppress inflammatory immune responses and to inhibit bacterial dissemination. We therefore believe that targeting of CD101 is a potential strategy for the treatment of autoimmune, inflammatory or infectious diseases.