David E. Anderson

CD4+ T helper 1 (TH1) cells are important mediators of inflammation and are regulated by numerous pathways, including the negative immune receptor Tim-3. We found that Tim-3 is constitutively expressed on cells of the innate immune system in both mice and humans, and that it can synergize with Toll-like receptors. Moreover, an antibody agonist of Tim-3 acted as an adjuvant during induced immune responses, and Tim-3 ligation induced distinct signaling events in T cells and dendritic cells; the latter finding could explain the apparent divergent functions of Tim-3 in these cell types. Thus, by virtue of differential expression on innate versus adaptive immune cells, Tim-3 can either promote or terminate TH1 immunity and may be able to influence a range of inflammatory conditions.

Linkage analysis of ten Utah kindreds and one Texas kindred with multiple cases of cutaneous malignant melanoma (CMM) provided evidence that a locus for familial melanoma susceptibility is in the chromosomal region 9p13-p22. The genetic markers analyzed reside in a candidate region on chromosome 9p21, previously implicated by the presence of homozygous deletions in melanoma tumors and by the presence of a germline deletion in an individual with eight independent melanomas. Multipoint linkage analysis was performed between the familial melanoma susceptibility locus (MLM) and two short tandem repeat markers, D9S126 and the interferon-alpha (IFNA) gene, which reside in the region of somatic loss in melanoma tumors. An analysis incorporating a partially penetrant dominant melanoma susceptibility locus places MLM near IFNA and D9S126 with a maximum location score of 12.71. Therefore, the region frequently deleted in melanoma tumors on 9p21 presumably contains a locus that plays a critical role in predisposition to familial melanoma.

TIM-3 is a molecule selectively expressed on a subset of murine IFN-gamma-secreting T helper 1 (Th1) cells but not Th2 cells, and regulates Th1 immunity and tolerance in vivo. At this time little is known about the role of TIM-3 on human T cells. To determine if TIM-3 similarly identifies and regulates Th1 cells in humans, we generated a panel of mAb specific for human TIM-3. We report that TIM-3 is expressed by a subset of activated CD4(+) cells, and that anti-CD3/anti-CD28 stimulation increases both the level of expression as well as the number of TIM-3(+) T cells. We also find that TIM-3 is expressed at high levels on in vitro polarized Th1 cells, and is expressed at lower levels on Th17 cells. In addition, human CD4(+) T cells secreted elevated levels of IFN-gamma, IL-17, IL-2, and IL-6, but not IL-10, IL-4, or TNF-alpha, when stimulated with anti-CD3/anti-CD28 in the presence of TIM-3-specific, putative antagonistic antibodies. This was not mediated by differences in proliferation or cell death, but rather by induction of cytokines at the transcriptional level. These results suggest that TIM-3 is a negative regulator of human T cells and regulates Th1 and Th17 cytokine secretion.