Mutual Activation and Expansion of Donor CD4 ⁺ T Cells and B Cells in Transplants Play a Critical Role in the Initiation of Chronic Graft-Versus-Host Disease.

Abstract 1342

Poster Board I-364

Chronic graft versus host disease (GVHD) is an autoimmune-like disease, in which both donor CD4⁺ T and B cells play important roles in the pathogenesis. However, it is unclear how donor CD4⁺ T and B cells interact in the context of chronic GVHD. In our current studies, we found that, in a new chronic GVHD model of MHC-matched DBA/2 donor to BALB/c host, depletion of donor CD4⁺ T cells in transplants prevented donor B220⁺ B cell upregulation of co-stimulatory molecules (i.e. B7.1, B7.2, and MHC II), prevented donor B cell differentiation into syndecan⁺ IgG anti-dsDNA autoantibody-producing plasma cells, and prevented the induction of chronic GVHD. In addition, we found that donor CD4⁺ T cells were able to drive both marginal zone B (AA4.1⁻B220⁺CD1d^hiCD23^lo) and follicular B (AA4.1⁻B220⁺CD23^hiCD1d^lo) cells to become IgG autoantibody-producing cells. On the other hand, depletion of donor B220⁺ B cells in transplants prevented expansion of donor-type CD4⁺ T cells that proliferated in response to donor DC stimulation, prevented the skewing of TCR CDR3-length of the donor CD4⁺ T cells as revealed by TCR spectratyping, and prevented induction of chronic GVHD. These results indicate that donor CD4⁺ T and B cells mutually activate each other in the chronic GVHD recipients; alloreactive donor CD4⁺ T cells activate and drive donor B cell differentiation into IgG autoantibody producing cells, in turn, donor B cells mediate the expansion and TCR-spreading of autoreactive donor CD4⁺ T cells. Therefore, donor CD4⁺ T and B cells in transplants orchestrate the development of chronic GVHD. This work is supported by NIH R01 AI066008.