Functional analysis and the molecular mechanism of CCR5 in the CTL induction.

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1. Chemokine receptors in the immunological synapse regulate the sensitivity of antigen recognition : CCR5 is predominantly expressed on resting memory T cells of which expression is enhanced on activated T cells. Although CCR5 is known as, a coreceptor of HIV, it has been suggested that CCR5 has also a function as a costimulatory molecule for leukocyte activation in vitro other than chemotaxis. To extend this idea, we have shown that CCR5 accumulated and actually was activated in the immunological synapse after TCR stimulation by evaluating BRET (Bioluminescence Resonance Energy Transfer) signals. Furthermore, a CCR5 antagonist, TAK-779 strongly inhibited human CD8+T cell proliferation by CD3 and CD28 coated plates and also LFA-1 inside-out signaling through Rapt after TCR stimulation. We confirmed that CCR5 and CXCR3 function as costimulatory molecules of T cells in vivo by developing double CCR5 and CXCR3 knockout mouse. Taken together, CCR5 and CXCR3 on CD8+T cells have a costimulatory signal or boosting signal with T cell receptor mediated-signal to regulate LFA-1 activation through Rapl in the immunological synapse. These findings explain a mechanism of recent report describing complete acceptance of kidney transplants in recipients with CCR5delta32 mutation.2.Blockade of GVHD by targeting chemokines and development of a way to selectively induce GVL/T : In an acute GVHD model, donor CD8T cells proliferated and differentiated in the secondary lymphoid organs and apoptosis of intestinal epithelium was induced at the crypts. Surprisingly, neutralizing antibodies against Fractalkine/MAdCAM-1 inhibited intestinal injury. When tumor cells P815 (H-2^d) were injected into BDF-1 (H-2^<bd>) and the splenocytes from C57BL/6 (H-2^b) were transferred to recipient mice, elongation of the survival of recipients was observed preserving GVL effect. Thus we propose a therapy for GVHD by targeting CX3CR-1-Fractalkine and a4b7-MadCAM-1 keeping GVL/T effect.