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Despite a long-standing hypothesis that chronic graft-versus-host disease (cGVHD) is an autoimmune disorder, most mouse models of cGVHD have been developed on the assumption that donor T cells are essential for its development. Here we show that cGVHD may be caused by autoreactive host T cells in mice that have been lethally irradiated and grafted with T-cell-depleted allogeneic bone marrow cells. In this chimera, host T cells derived from radioresistant intrathymic T-cell precursors caused dermal fibrosis and periportal inflammation, without the requirement for donor T cells. The lack of host DCs within the thymus after high-dose irradiation allowed autoreactive host T cells to escape thymic negative selection. Moreover, the homeostatic expansion of these T cells may augment their autoreactivity. These findings indicate that host T-cell-mediated cGVHD is an autoimmune process that occurs following the grafting of T-cell-depleted BM cells into hosts with functioning thymuses. We propose, based on the present data, that host T-cell-dependent autoimmunity is a potential mechanism by which cGVHD is induced.

Recently, a novel CD4(+) T-cell developmental pathway was reported that generates thymocyte-thymocyte (T-T) CD4(+) T cells. We established a mouse system (CIITA(tg)CIITApIV(-/-)) where thymic positive selection occurred only by major histocompatibility complex (MHC) class II(+) thymocytes. T-T CD4(+) T cells selected via MHC class II-dependent T-T interaction are comprised of PLZF-negative and innate PLZF-positive populations. Until recently, the functional role of the PLZF-negative population was unclear. In this study, we demonstrate that naïve T-T CD4(+) T cells provide B-cell help to a level comparable with that of naïve conventional CD4(+) T cells. Considering the absence of PLZF expression in naïve T-T CD4(+) T cells, these results suggest that PLZF-negative naïve T-T CD4(+) T cells are functionally equivalent to conventional naïve CD4(+) T cells in terms of B-cell help.

Unlike conventional T cells, innate-like T cells such as natural killer (NK) T cells are selected by homotypic T-cell interactions. Recently, a few reports have shown that T-T CD4(+) T cells can be generated in a similar manner to that for NKT cells. These two types of cells share common functional properties such as rapid response to antigenic encounters and the potential for a panoply of cytokine secretion. However, T-T CD4(+) T cells differ from NKT cells in that they are restricted by highly polymorphic major histocompatibility complex (MHC) II molecules and have a diverse T-cell receptor repertoire. Additional example of T-T interactions was recently reported in which peripheral T cells re-circulate to the thymus and participate in the thymocyte selection process. In this review, we dissect the cellular mechanisms underlying the production of T-T CD4(+) and NKT cells, with particular emphasis on the differences between these two T-cell prototypes. Finally, we propose that T-T CD4(+) T cells serve two major functions: one as an acute-phase reactant against viral infection and the other is the generation of anti-ergotypic CD4(+) T cells for regulatory purposes. All of these features make it possible to create a diverse set of functional cells through MHC class II-restricted T-T interactions.