Proximal signaling control of human effector CD4 T cell function

The functional coupling of T cell receptor (TCR)-mediated signaling events in primary human T cells remains undefined. We demonstrate here that alterations in the expression of proximal TCR-coupted signaling subunits are associated with distinct effector capacities in differentiated human CD4 T cells. Analysis of proximal signaling profiles using biochemical and single cell approaches reveals decreased 03 and ZAP-70 expression correlating with functional anergy, with increased CD3 zeta/ ZAP-70 expression and phosphorylation connoting acquisition of effector capacity. By contrast, the FcR gamma signaling subunit known to be expressed in human effector cells and in T cells from the autoimmune disease SLE is up-regutated upon activation, yet does not correlate with functional capacity in effector cells, and does not alter signaling or function in primary FcR gamma transfectants. Our results have implications for targeting signaling molecules in immunotherapy and evaluating the functional consequence of signaling alterations associated with autoimmunity and chronic diseases. (c) 2007 Elsevier Inc. All rights reserved.