Growing evidence from several murine models suggests that STAT3 signaling in CD4+ T-cells plays a pivotal role in the pathogenesis of autoimmunity. We herein tested the hypothesis that the same pathway plays a critical role in the induction of GVHD in murine models of allogeneic BMT. To test our hypothesis and to compare the differential ability of STAT3 signaling in CD4+ T-cells to mediate GVHD in MHC-mismatched and-matched murine models of alloBMT, CD4-Cre × STAT3flox/flox (STAT3KOCD4+), or corresponding wild-type control mice were used as donors of CD4+ T-cells. In an MHC-mismatched model, groups of lethally irradiated (775 cGy) BALB/c (H-2d) mice received T-cell depleted (TCD) bone marrow (BM) from wild-type C57BL/6 (H-2b) mice alone, TCD B6 BM plus 4 × 105wild-type, or STAT3KOCD4+ T-cells, all on a C57BL/6 background. In repeated experiments we observed significantly decreased clinical signs of GVHD in animals receiving STAT3KOCD4+ in comparison to those receiving wild-type CD4+ T-cells (median GVHD score of 2.25 vs. 5.29; P <.001) but no difference in lethality in chimeras monitored up to day 60 posttransplant. In an MHC-matched, minor histocompatibility mismatched setting, we conducted experiments using the B10.D2 (H-2d) BALB/c (H-2d) model in which GVHD is CD4+ T-cell-mediated and has clinicopathologic consistent with human chronic GVHD. Since the dominant clinical manifestation in this model is cutaneous sclerodermatous GVHD that is associated with in situ dermal mononuclear infiltrates, the use of BALB/c-CD45.1 (CD45.1+) mice as recipients enabled us to examine the fate of skin CD11c+ dendritic cells. After conditioning (775 cGy) recipient mice received B10.D2 (CD45.2+) TCD BM and 9.3 ×106 TCD splenocytes, repleted with 106 wild-type CD8+ and 1.9 ×106 wild-type, or STAT3KOCD4+ T-cells. We reproducibly induced all signs of chronic GVHD in chimeras receiving wild-type CD4+ T-cells, but not in chimeras injected with STAT3KOCD4+ T-cells (median GVHD score of 5.2 vs. 0.0; P <.001). We found that development of cutaneous GVHD was accompanied by prominent dermal infiltration of donor-derived inflammatory monocytes and complete turnover to donor CD11c+ epidermal DC chimerism (88.4±4.3% vs. 0.9±0.6%; P <.001). Interestingly, splenic CD11c+ DC (99.9±0.1% vs. 99.8±0.1%), CD4+ (99.9±0.2% vs. 99.6±0.7%) and CD8+ (99.9±0.2% vs. 99.9±0.2%) T-cell chimerism was nearly completely donor-derived and did not differ between the two sets of described chimeras. In summary, our data suggest that intact STAT3 signaling in CD4+ T-cells is required for clinical manifestations of delayed acute and/or chronic GVHD, but it does not interfere with lymphohematopoietic graft-versus host response and achievement of full donor chimerism. Further exploration of the STAT3 signaling pathway in pathophysiology of delayed acute and/or chronic GVHD is warranted.
Disclosure: No relevant conflicts of interest to declare.