Lymph Node Stromal Fiber ER-TR7 Modulates CD4+ T Cell Lymph Node Trafficking and Transplant Tolerance

Abstract

Background Trafficking and differentiation of naïve CD4+ and regulatory T cells (Treg) within the lymph node (LN) are integral for tolerance induction. The LN is comprised of stromal fibers that dictate lymphocyte migration and LN structure, organization, and microanatomic domains. Distribution of the stromal fiber ER-TR7 changes within the LN following antigenic challenge, but the contributions of ER-TR7 to the resulting immune response remain undefined. We hypothesized that these stromal fiber structural changes affect T cell fate and subsequently allograft survival. Methods C57BL/6 mice were left naïve (untreated) or made immune or tolerant (donor-specific BALB/c splenocyte transfusion −/+ anti-CD40L mAb), or made tolerant and received anti-ER-TR7 mAb. Donor-specific T cell migration was visualized by adoptive transfer of CFSE-labeled TEa T cell receptor transgenic CD4+ cells. Immunohistochemistry was performed on lymph nodes to detect stromal fiber distribution, structure, CCL21 presence, and Treg and donor-specific cell location relative to high endothelial venules (HEV). Naïve, tolerant, and tolerant + anti-ER-TR7 mice received BALB/c heterotopic cardiac allografts and graft survival was monitored. Results ER-TR7 distribution changed following the induction of tolerance vs. immunity. Treating tolerant mice with anti-ER-TR7 altered HEV basement membrane structure and the distribution of CCL21 within the LN. These differences were mirrored by changes in the migration of naïve and Treg cells within and surrounding the HEV. Anti-ER-TR7 prevented tolerance induction and resulted in allograft inflammation and rejection. Conclusions These results identify ER-TR7 as an important component of LN structure in tolerance and a direct target for immune modulation.

IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance

“…These fibers and networks not only help in the migration of T cells, B cells and APCs; but also provide a platform for cognate interactions which play important roles in shaping immunity and tolerance [49]. Reagents that disrupt the stromal fiber network prevent the generation and maintenance of transplantation tolerance [50,51]. Our present results showed that B cell depletion alters the migration and distribution of Tfh and Tfr in specific cellular compartments of the secondary lymphoid organs.…”

Role of lymph node stroma and microenvironment in T cell tolerance

“…96 Tregs are recruited around the HEV and CR under tolerogenic compared to immune conditions. 96 Tregs are recruited around the HEV and CR under tolerogenic compared to immune conditions.…”

“…96,[113][114][115] Laminin 411 and 511 serve as coinhibitory and costimulatory li- Laminin α4 is associated with tolerance and laminin α5 is associated with immunity. Laminin α4 increases in response to tolerance induction, increasing the laminin α4:α5 ratio.…”

“…Notable structural changes to HEV include increased complexity of ERTR-7 fibers surrounding the abluminal surface of the HEVs which facilitates Treg migration. 96 Tregs are recruited around the HEV and CR under tolerogenic compared to immune conditions. 97 initiating cellular death.…”

“…Conversely, upregulation of laminin α5 occurs in response to immunity and inflammation, decreasing the laminin α4:α5 ratio. 96,[113][114][115] Laminin 411 and 511 serve as coinhibitory and costimulatory ligands for CD4 T cells, respectively. Laminin 411 suppresses CD4 T cell activation and Th1, Th2, and Th17 polarization, but favors iTreg polarization; laminin 511 displays the opposite effect on CD4 T cell differentiation.…”