Présentation d'antigènes, maladies autoimmunes et tolérance périphérique des lymphocytes T
Lymph nodes (LNs) are specialized organs draining the lymph flow and orchestrating antigen (Ag) specific adaptive immunity. LN stromal cells (LNSCs) release soluble factors that facilitate the migration and interactions between hematopoietic cells, and the homeostasis of immune cells. In addition, two particular subtypes, the fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs), express Ags otherwise restricted to a small number of peripheral tissues. Direct presentation of peripheral tissue Ags (PTAs) by LECs and FRCs to self-reactive CD8+ T cells results in their abortive proliferation and deletion. Therefore, LECs and FRCs exhibit functions in LNs similar to that of medullary thymic epithelial cells (mTECs) to maintain CD8+ T cell tolerance. Our laboratory is more focused on the LEC subset. Major histocompatibility complex class II (MHCII) molecules are expressed at low levels by LECs in steady-state, and are upregulated under inflammatory conditions. Our recent studies demonstrate that the loss of MHCII expression in murine LNSCs impairs peripheral CD4+ T cell tolerance, and alters regulatory T cell (Treg) populations, resulting in signs of spontaneous autoimmunity in aged mice. We are deciphering how MHCII-restricted antigen presenting LECs impact self-reactive CD4+ T cell responses, and in particular, the implication of a non-classical Ag presentation pathway, autophagy, in this process. By selectively abrogating MHCII expression and autophagy in LECs, we aim to determine the consequences on the self-reactive CD4+ T cell responses and the induction of autoimmunity.
Lymphatic vessels are known to transport soluble Ags. We are testing the ability of LECs to capture exogenous Ags and present them to T cells. Importantly, during tumor progression, LECs substantially expand and, consequently, lymphatic drainage is increased in the tumor itself and draining LNs. Therefore, the ability of LECs to capture Ags will be potentially enhanced in a tumoral context. Our ongoing work deciphers the role of Ag-presentation by LECs in tumor-associated immunity. We are dissecting the molecular features of tumor-associated LECs and their ability to present tumor Ags to CD4+ T cells. The selective abrogation of their Ag presenting functions allows us to study the impact on anti-tumor T cell immunity and, thus, tumor growth progression. Finally, studies have shown that FRCs and LECs are strongly modulated by inflammation or infections, reflecting a possible phenotypic and functional specialization of those cells depending on the organ and the immune microenvironment. As such, our goal is to identify key molecules that are specifically regulated by LECs in the tumor microenvironment (TME) and are implicated in the modulation of host immunity to the tumor. We hypothesise that the lymphatic endothelium in the local TME may be a strategy for targeted immunotherapy.