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Novel Role of Qa-1, a Murine Homolog of HLA-E, in Controlling Follicular Helper T Cells During Humoral Alloimmunity

J. Y. Choi1, S. K. Eskandari1, S. Cai1, J. Assaker1, I. Sulkaj1, H. Allos1, J. Alhaddad1, P. Chu1, H. Kim2, H. I. Cantor2, J. R. Azzi1

1Medicine, Brigham and Women's Hospital, Boston, MA, 2Immunology, Dana Farber Cancer Institute, Boston, MA

Meeting: 2020 American Transplant Congress

Abstract number: 611

Keywords: Alloantibodies, Major histocompatibility complex (MHC), Mice, knockout, Rejection

Session Information

Session Name: Lymphocyte Biology: Signaling, Co-Stimulation, Regulation

Session Type: Oral Abstract Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:45pm

 Presentation Time: 3:27pm-3:39pm

Location: Virtual

*Purpose: Antibody-mediated rejection (AMR) is a major challenge in prolonging allograft survival. Limited insight into the humoral alloimmunity hinders the development of therapeutic strategies. We showed that a non-classical MHC called Qa-1 (HLA-E in human) is highly expressed on follicular helper T cells (TFH) during rejection. Qa-1 transduces dichotomous signaling on regulatory CD8 T cells (CD8 Treg) by binding either 1) T cell receptor (TCR) that activates, or 2) NKG2A receptor that inhibits CD8 Treg lytic function. Using transgenic mice B6.Qa-1D227K (D227K), which harbor a mutation that specifically inhibits binding of Qa-1 to CD8 TCR, we showed the critical role of CD8 Treg in controlling TFH and AMR.

*Methods: BALB/c heart allografts were transplanted into B6 (WT) or D227K recipients with either single- or multiple-doses of CTLA4-Ig for mechanistic and survival analysis. For mechanistic, recipients’ spleens, serum and allografts were analyzed for immunophenotype, donor-specific antibody (DSA) and histopathology. Tconv (CD25+CD4+) isolated from either WT or D227K and CD8 Treg (CD44+CXCR5+CD8+) from naive WT were either 1) co-cultured with stimulation, or 2) adoptively trasnferred to RAG1-/- hosts, for in vitro and in vivo suppression assay.

*Results: We showed that Qa-1 is highly upregulated on TFH compared to whole CD4+T cells (18.5-fold, P<0.001) [Fig. (A)]. D227K recipients showed increased frequency of TFH, isotype-switched B cells and plasmacytes compared to WT recipients (fold difference: 2.0, 2.5, 2.2 and P<0.05, 0.01, 0.05, respectively) [Fig. (B)]. These findings were associated with 11-fold higher DSA in D227K compared to WT (P<0.001) [Fig. (C)]. Allografts from D227K showed severe structural damage, vessel injury and strong C4d deposition, in contrast to allografts from WT [Fig. (D)]. Tolerance induction was abrogated in D227K recipients (allograft survival: 25 days vs 98 days, D227K vs WT respectively, P<0.001). Finally, CD4+ T cells isolated from WT but not D227K were sensitive to killing by CD8 Treg in vivo [Fig. (E)] and in vitro [Fig. (F)].

*Conclusions: We showed that 1) disrupting the CD8 Treg function unleashes TFH leading to severe AMR, while 2) killing of activated CD4+ T cells and TFH by CD8 Treg is Qa-1-dependent both in vivo and in vitro. We will extend theses findings by specifically inhibiting the Qa-1-NKG2A receptor interaction to enhance killing of TFH by CD8 Treg, thus protecting allografts from AMR.

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To cite this abstract in AMA style:

Choi JY, Eskandari SK, Cai S, Assaker J, Sulkaj I, Allos H, Alhaddad J, Chu P, Kim H, Cantor HI, Azzi JR. Novel Role of Qa-1, a Murine Homolog of HLA-E, in Controlling Follicular Helper T Cells During Humoral Alloimmunity [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/novel-role-of-qa-1-a-murine-homolog-of-hla-e-in-controlling-follicular-helper-t-cells-during-humoral-alloimmunity/. Accessed May 9, 2025.

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