B Lymphocytes, Potent Antigen Presenting Cells for Preferential Expansion of Allo-Reactive FoxP3 CD4 Regulatory T Cells

摘要

Abstract: The naturally arising FoxP3+ CD4 T (nTr) cells are absolutely required for the induction and maintenance of nimmunological tolerance to self antigens. In addition to their physiological role, nTr cells can also be utilized effectively nfor treatment of autoimmune diseases, allograft rejection and graft versus host disease in animal models. Due to the very nlow frequency in the peripheral blood, nTr cells need to be expanded in ex vivo to generate sufficient numbers for ntherapeutic applications. The nTr cells can be expanded either polyclonally using anti-CD3/CD28 antibodies, or in an nalloantigen-specific manner using allogeneic antigen presenting cells. The allospecific nTr cells are more therapeutically neffective with less risk to cause non-specific immune suppression as compared to polyclonal nTr cells. Despite the success nin expanding murine nTr cells, little success has been achieved in expanding human allospecific nTr cells, posing a major nbarrier to the development of nTr cell-based immunotherapy in humans. We have found that mouse B cells preferentially nactivate and induce expansion of nTr cells in allogeneic mixed lymphocyte reactions. The preferential expansion of nFoxp3+n T ncells can be further enhanced by a partial blockade of class IIn nMHC-TCR interaction, suggesting that nTr cells npreferentially respond to weak TCR stimulation. Extending the findings with murine B cells, we have further found that nhuman B cells can efficiently expand allogeneic human nTr cells ex vivo. The expanded nTr cells expressn nvery high levels nof FoxP3, maintain an anergic phenotype, and aren npotent suppressor cells capable of inhibiting the alloreactivity nof third-nparty responder T cells at very low nTr-to-T effectorn ncell ratios in an alloantigen-specific manner. The allospecificity npossessed by the B cell-expanded nTr cells is notn ndetermined by the HLA haplotypes of the nTr cells, but it isn ninduced and ndetermined by the HLA haplotype of the B cells used nto expand nTr cells. Our findings represent a significant advancen nin nthe development of nTr cell-based immunotherapy in humansn nand raise the possibility of using “off-the-shelf” third-party nnTr cells forn ntherapeutic applications. This review also outlines some patents on immunotherapy.