Introduction: Lymphoid neogenesis has been found in allografts after organ transplant. We previously reported that spontaneously accepted DBA/2 to B6 kidney allografts developed distinctive, peri-arterial sheaths containing numerous Foxp3+ cells, which we have termed as TOLS. Here we investigated the time-course, cellular composition and functional properties of TOLS.

Methods: DBA/2 to B6 kidney allografts at different time points post-transplant were used to characterize evolution and phenotype of graft cell infiltrates. CCR7 and lymphotoxin-α(LT) knockout, and LTβR-Ig treated WT recipients were used to study possible underlining mechanisms of TOLS formation.

Results: Renal grafts showed massive peri-arterial infiltrates at week 1. By week 6 these infiltrates were seen as TOLS around arteries. Podoplanin expression was observed in TOLS by week 6, indicating the presence of lymphatics and lymphoid structural characteristics. Unlike tertiary lymphoid organs (TLOs) associated with chronic inflammation, TOLS were PNAd- and lacked germinal centers. T cells, Tregs, B cells, conventional DCs, plasmacytoid DCs and CD11b+ cells were the major immune cell types found in TOLS. FACS analysis showed the majority of T cells in TOLS were CD44^highCD62L^– effector memory T cells. More than 90% of T cells expressed PD-1 and TIGIT. We further found approximately 20% of CD4+ T cells in TOLS were Foxp3+, 35% of these Foxp3+ cells were Ki-67+, and in contrast only 6% of other T cells were Ki-67+. Initial data of a DBA/2 kidney transplanted into CCR7 KO recipient showed rejection and lack of TOLS formation by day21. TOLS were also seen in LTα knockout recipients which lack lymph nodes. Treatment of WT recipients with LTβR-Ig did not inhibit development of TOLS nor disrupt well formed TOLS.

Conclusion: Accepted renal allografts gradually develop novel ectopic lymphoid structures termed TOLS by week 6. Unlike TLOs associated with chronic inflammation, both development and maintenance of TOLS is independent of LTα and LTβ signaling but is highly dependent on CCR7. TOLS demonstrate a tolerogenic phenotype distinct from TLO and we propose are a manifestation and a mechanism of regulatory tolerance.

CITATION INFORMATION: Yang C, Rosales I, Farkash E, Ndishabandi D, White R, Russell P, Madsen J, Alessandrini A, Colvin R. Early Evolution and Immunopathologic Phenotype of Treg-Rich Organized Lymphoid Structures (TOLS) Associated with Immunological Tolerance in Accepted Mouse Kidney Allografts. Am J Transplant. 2017;17 (suppl 3).

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