Investigating the process and regulation of thymocyte egress by lymphotoxin beta receptor and thymic stroma

James, Kieran David Jon (2018). Investigating the process and regulation of thymocyte egress by lymphotoxin beta receptor and thymic stroma. University of Birmingham. Ph.D.

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Abstract

The thymus is a heterogeneous mix of hematopoietic and stromal cells that function to generate a functional, self-tolerant T-cell pool. Although many of these populations are well studied, the role of non-epithelial stroma remains unclear.

Thymic mesenchyme has been identified as an important regulator of T-cell egress. Studies of lymphotoxin beta-receptor (LT $\beta$ R) have revealed its critical role in T-cell egress as well as the development and function of lymph node mesenchyme. We hypothesized that (LT $\beta$ R) regulation of thymic mesenchyme is critical forT-cell egress. To test this we generated $Wnt-1^{cre}Ltbr^{flox}$ mice to delete (LT $\beta$ R) on thymic mesenchyme and revealed this to be non-essential forT-cell egress. Moreover, we generated $Foxn-1^{cre}Ltbr^{flox}$ mice to delete (LT $\beta$ R) on thymic epithelial cell (TEC). Despite the critical role of (LT $\beta$ R) in medullary TEC development, T-cell egress was normal. However, deleting (LT $\beta$ R) on thymic endothelium using $Flk-1^{cre}Ltbr^{flox}$ mice revealed an essential role of (LT $\beta$ R) regulation of endothelium to control T-cell egress. Our analysis also revealed that T-cell entry into the perivascular space during T-cell egress occurs stochastically. Collectively our findings highlight a novel role for (LT $\beta$ R) regulation of thymic endothelium as a critical pathway of T-cell egress.