Equal Expansion of Endogenous Transplant-Specific Regulatory T Cell and
Recruitment Into the Allograft During Rejection and Tolerance
#MMPMID29973932
Young JS
; Yin D
; Vannier AGL
; Alegre ML
; Chong AS
Front Immunol
2018[]; 9
(?): 1385
PMID29973932
show ga
Despite numerous advances in the definition of a role for regulatory T cells
(Tregs) in facilitating experimental transplantation tolerance, and ongoing
clinical trials for Treg-based therapies, critical issues related to the optimum
dosage, antigen-specificity, and Treg-friendly adjunct immunosuppressants remain
incompletely resolved. In this study, we used a tractable approach of MHC
tetramers and flow cytometry to define the fate of conventional (Tconvs) and
Tregs CD4(+) T cells that recognize donor 2W antigens presented by I-A(b) on
donor and recipient antigen-presenting cells (APCs) in a mouse cardiac allograft
transplant model. Our study shows that these endogenous, donor-reactive Tregs
comparably accumulate in the spleens of recipients undergoing acute rejection or
exhibiting costimulation blockade-induced tolerance. Importantly, this expansion
was not detected when analyzing bulk splenic Tregs. Systemically, the
distinguishing feature between tolerance and rejection was the inhibition of
donor-reactive conventional T cell (Tconv) expansion in tolerance, translating
into increased percentages of splenic FoxP3(+) Tregs within the 2W:I-A(b) CD4(+)
T cell subset compared to rejection (~35 vs. <5% in tolerance vs. rejection). We
further observed that continuous administration of rapamycin, cyclosporine A, or
CTLA4-Ig did not facilitate donor-specific Treg expansion, while all three drugs
inhibited Tconv expansion. Finally, donor-specific Tregs accumulated comparably
in rejecting tolerant allografts, whereas tolerant grafts harbored <10% of the
donor-specific Tconv numbers observed in rejecting allografts. Thus, ~80% of
2W:I-A(b) CD4(+) T cells in tolerant allografts expressed FoxP3(+) compared to
?10% in rejecting allografts. A similar, albeit lesser, enrichment was observed
with bulk graft-infiltrating CD4(+) cells, where ~30% were FoxP3(+) in tolerant
allografts, compared to ?10% in rejecting allografts. Finally, we assessed that
the phenotype of 2W:I-A(b) Tregs and observed that the percentages of cells
expressing neuropilin-1 and CD73 were significantly higher in tolerance compared
to rejection, suggesting that these Tregs may be functionally distinct.
Collectively, the analysis of donor-reactive, but not of bulk, Tconvs and Tregs
reveal a systemic signature of tolerance that is stable and congruent with the
signature within tolerant allografts. Our data also underscore the importance of
limiting Tconv expansion for high donor-specific Tregs:Tconv ratios to be
successfully attained in transplantation tolerance.
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