Regulatory mechanisms in immune responses

Abstract

CD4 Foxp3 T cells are well-defined regulatory T (TR) cells that develop in the thymus through positive selection by medium-to-high affinity T cell receptor (TCR)-major histocompatibility (MHC) interactions. TR cells play an important role in autoimmunity, allergy, tumor immunity and organ transplantation. In the first part of this work, it is described that Foxp3 TR cells can be generated in the complete absence of MHC class II molecules. CD4 Foxp3 TR cells were found in lymph nodes, spleen, liver but not thymus of MHC class II-deficient (Aalpha-/-) C57BL/6J (B6) mice that were apparently generated in the periphery (inducible TR cells). These Foxp3 TR cells are preferentially expressing the cell surface molecule CD103 but not CD25 (that is highly expressed by thymus-dependent, natural TR cells). MHC class II-independent Foxp3 TR cells downmodulate T cell responses in vivo and in vitro with similar efficiency than those from congenic, wild-type B6 mice. Hence, Aalpha-/- mice are a novel model for the study of inducible Foxp3 TR cells. Only small populations of non-activated, non-proliferating Foxp3 TR cells are found in the non-parenchymal cell compartment of the mouse liver. Local increase of intrahepatic, regulatory CD4 Foxp3 TR cells is found in patients with chronic viral infection (i.e. hepatitis B virus or hepatitis C virus infection) or hepatocellular cancer. In the second part of this work, I show that specific or polyclonal T cell activation induces the accumulation of activated and proliferating regulatory T cells in the liver. Although it contains only a small, resident population of quiescent, local CD4 Foxp3 TR cells, the liver can hence rapidly mobilize and/or recruit this T cell control in response to the local accumulation of peripherally or locally activated CD8 T cells.