AUTHOR=Hall Bruce M. , Robinson Catherine M. , Plain Karren M. , Verma Nirupama D. , Tran Giang T. , Nomura Masaru , Carter Nicole , Boyd Rochelle , Hodgkinson Suzanne J. TITLE=Changes in Reactivity In Vitro of CD4+CD25+ and CD4+CD25− T Cell Subsets in Transplant Tolerance JOURNAL=Frontiers in Immunology VOLUME=8 YEAR=2017 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.00994 DOI=10.3389/fimmu.2017.00994 ISSN=1664-3224 ABSTRACT=

Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4⁺CD25⁺ T cells, yet in many models, proliferation of CD4⁺ T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4⁺, CD4⁺CD25⁺, and CD4⁺CD25⁻ T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naïve DA rats were examined. Proliferation of CD4⁺ T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells. In mixed lymphocyte culture to PVG, proliferation of naïve CD4⁺CD25⁻ T cells was greater than naïve CD4⁺ T cells. In contrast, proliferation of CD4⁺CD25⁻ T cells from tolerant hosts to specific-donor PVG was not greater than CD4⁺ T cells, whereas their response to Lewis and self-DA was greater than CD4⁺ T cells. Paradoxically, CD4⁺CD25⁺ T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naïve CD4⁺CD25⁺ T cells proliferate to both PVG and Lewis but not to self-DA. CD4⁺CD25⁺ T cells from tolerant, but not naïve hosts, expressed receptors for interferon (IFN)-γ and IL-5 and these cytokines promoted their proliferation to specific-alloantigen PVG but not to Lewis or self-DA. We identified several differences in the patterns of proliferation to specific-donor alloantigen between cells from tolerant and naïve hosts. Most relevant is that CD4⁺CD25⁺ T cells from tolerant hosts failed to proliferate or suppress to specific donor in the absence of either IFN-γ or IL-5. The proliferation to third-party and self of each cell population from tolerant and naïve hosts was similar and not affected by IFN-γ or IL-5. Our findings suggest CD4⁺CD25⁺ T cells that mediate transplant tolerance depend on IFN−γ or IL-5 from alloactivated Th1 and Th2 cells.