"Lag-3 Mediates Acute Rejection & Memory In Mouse Transplantation" by Jeffrey Mark Erfe

Date of Award

January 2018

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

George Tellides

Abstract

Lymphocyte Activation Gene-3 (LAG-3) is a soluble protein and transmembrane protein receptor expressed on lymphocytes such as immunosuppressive regulatory T cells. Our goal was to evaluate the effect of LAG-3 on transplantation outcomes, specifically rejection and cellular memory response to donor antigen, by comparing graft survival and IFN-l secretion to donor antigen in C57BL/6 LAG-3-/- versus wild-type mouse recipients of DBA/2 grafts. We found that LAG-3 deletion accelerates rejection time and enhances IFN-l secretion among heart or skin graft recipients. FACS analysis of memory T cells demonstrated disproportionate increases in effector T cell subsets, consistent with a heightened rejection response. Although the absence of LAG-3 enhanced rejection of heart and skin grafts, it did not abrogate tolerance of spontaneously accepted kidney allografts. To further understand the mechanism of LAG-3 signaling and the potential importance of dendritic cells, we cultured donor dendritic cells in a tolerogenic milieu with recipient T cells and found increased PD-1 and IL-10 expression among T cells. Lastly, we performed soluble LAG-3 injections and adoptive transfers of LAG-3+/+ cells into knock-out graft recipients. This demonstrated that the presence of LAG-3 on T cells is critical for mediation of rejection, while LAG-3 on dendritic cells downregulates donor-specific IFN-l secretion. Our data suggest that in addition to LAG-3’s effects on proliferation and activation, LAG-3 may also affect differentiation of precursor CD4+ T cells. Additionally, these data indicate the importance of dendritic cell-mediated control of the memory response in a LAG- 3-dependent manner.

Comments

This is an Open Access Thesis.

Open Access

This Article is Open Access

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