Leukocyte Associated Immunoglobulin-Like Receptor 1 inhibits Th1 But Enhances Th17 Responses

V. Agashe,¹ M. Keller,² L. Haynes,¹ E. Jankowska-Gan,¹ J. Sullivan,¹ J. Kernien,¹ H. Suzuki,³ D. Wilkes,⁴ W. Burlingham.¹

¹Surgery, UW Madison, Madison, WI
²Tulane University, New Orleans, LA
³Chiba Graduate School of Medicine, Chiba, Japan
⁴Indiana University School of Medicine, Indianapolis, IN.

Meeting: 2015 American Transplant Congress

Abstract number: 140

Keywords: knockout, Mice, T cell activation, T cell reactivity, T helper cells

Topic:

Session Information

Session Name: Concurrent Session: T Cell Biology

Date: Sunday, May 3, 2015

Session Time: 4:00pm-5:30pm

Presentation Time: 4:12pm-4:24pm

Location: Room 119-B

Background: Leukocyte Associated Immunoglobulin-like Receptor 1 (LAIR1), is a transmembrane receptor expressed by immune cells. It recognizes collagen repeats via its extracellular domain and has two immunoreceptor tyrosine-based inhibitory motifs in its intracellular tail, making it an inhibitory receptor. Crosslinking of LAIR1 inhibits cellular functions of Natural Killer cells. C1q, because of its collagen tail, has been identified as a LAIR1 ligand, important in inhibiting dendritic cell differentiation. Recently, we showed that the P2X7, a receptor for extracellular ATP, was required for Th17 but not for Th1 immune response, implying different modes of activation in these cells. Hypothesis: T helper (Th)1 and Th17 responses will have different sensitivities to LAIR1 ligation in vivo, and therefore will differ in response to elevation in C1q. Results: For studying the role of LAIR1 in vivo we obtained LAIR1 knockout (KO) mice and used them in a Th17/Interleukin 17 based minor mismatch model of chronic rejection. Heterotrophic cardiac and orthotophic left lung transplantation between a B10 donor and B6 LAIR1 KO or wild type (WT) recipient revealed, less cellular infiltration and lower collagen deposition around the blood vessels and the airways of KO mice. These results supported our hypothesis, but run contrary to the view of LAIR1 as purely inhibitory. To directly compare effects on Th1 vs Th17 response, we utilized a trans-vivo delayed type hypersensitivity assay. First we used, a recombinant soluble sLAIR1/Fc protein, as a LAIR1 antagonist. Addition of sLAIR1/Fc, increased Th1 response to tetanus in a dose dependent manner, but decreased Th17 response to ColV peptides. Second, we utilized C1q, which decreased Th1 response to tetanus, but had no effect on Th17 ColV peptide response. Conclusion: The results support the hypothesis of LAIR1 being an important component of an in vivo Th17 response while strongly inhibiting Th1 response. Early after transplantation maintaining high levels of C1q could be beneficial in controlling early acute rejection, which is strongly Th1-biased. However over time therapeutics could be aimed at P2X7 receptor inhibition, which could lead to better control of the Th17 biased chronic rejection.

To cite this abstract in AMA style:

Agashe V, Keller M, Haynes L, Jankowska-Gan E, Sullivan J, Kernien J, Suzuki H, Wilkes D, Burlingham W. Leukocyte Associated Immunoglobulin-Like Receptor 1 inhibits Th1 But Enhances Th17 Responses [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/leukocyte-associated-immunoglobulin-like-receptor-1-inhibits-th1-but-enhances-th17-responses/. Accessed July 30, 2021.

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