Our long-term goal is to increase our understanding of the requirements for GVH. HVHD is caused by clonal expansion of donor T cells with the appropriate T cell receptor (TCR) for host alloantigen recognition. Productive expansion requires signaling via the TCR followed by a second (costimulatory) signal, typically delivered by antigen-presenting cells (APCs). By precluding the delivery of costimulatory signals to T cells triggered by host alloantigens, a subset of T cells will become tolerant leaving the remaining T cells unaffected and available for responses. Previously, we demonstrated that the function of the B7- CD28/CTLA-4 pathway determines the outcome of GVH responses. Positive signals for expansion may be provided by B7-1 or B7-2 present on APCs to CD28 present on T cells. B7 expression also is upregulated on donor T cells during a GVH response. The role of B7 signaling of donor T cells in the GVH response will investigated in aim 1. In other settings, it has been shown that negative signals may be provided by B7 binding to its T cell counterreceptor, CTLA-4. The role of CTLA-4 inregulating GVH responses will bee investigated. Cognate T cell: B cell interactions activate B cells to express B7 ligands, converting resting B cells from nonprofessional into professional APCs. A key event is CD40 binding to its counterreceptor, CD40 ligand (CD40L). Our studies have shown that CD40L is upregulated on T cells during a GVH response and blockade odelays and reduces GVH generation.
Aim 2 will determine how CD40-CD40L binding events affect B7- CD28/CTLA-4 regulation of alloresponses. Recent studies have shown that the upregulation of CD44H on APCs by CD40 signaling results in B cell mediated T cell costimulation independent of B7- CD28 binding. We will determine whether CD44 expression on host APCs is essential for alloresponses and GVH when B7-CD28 interaction is intact or is not possible. These studies will be accomplished by using a unique set of published and uppublished reagents available to us including mAbs directed toward T cell or APC costimulatory antigens and mice that overexpress or have deletions of antigens that might regulate costimulation. Collectively, these data will further our understanding of the biology of alloresponses which may be used to design new GVH preventive approaches.
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