Tolerance and autoimmunity
Cytotoxic T lymphocytes are one the principal effector populations of the adaptive immune system and play a key role in the defense against pathogens. The diversity of their TCR repertoire assures recognition of the vast majority of potential infectious agents. However, an important consequence of this diversity is the risk of pathogenic anti-self responses. Although the immune system has developed mechanisms of peripheral tolerance that prevent self-reactivity, CD8+ T cells may become activated, under conditions not yet well understood, resulting in autoimmunity. Many T cell-mediated autoimmune diseases have an extremely complex etiology with multiple genetic and environmental factors contributing to disease. This indicates that CD8+ T cells need to override multiple checkpoints, including the requirements for activation signals for antigen presenting cells, CD4+ T helper cells and bypassing regulatory T cell suppression and molecular negative T cell regulators, in order to become pathogenic effectors. Understanding these control mechanisms is essential to open new opportunities for therapeutic interventions in autoimmunity as well as cancer immunotherapy, since the latter is generally limited by tolerance.
Utilizing transgenic mouse models, our research interests focus on: i) understanding the mechanisms involved in the tolerization of CD8+ T cells upon they encounter self-antigens expressed in the pancreas and ii) understanding how these mechanisms of tolerance fail resulting in the generation of pathogenic effector T cell responses and autoimmune diabetes.
- Villard M et al. The role of lymphopenia-induced proliferation in the breakdown of peripheral CD8+ T cell tolerance. (2013) Submitted for publication.
- Álvarez-Vallina L et al. New trends in immunotherapy. (2011). Inmunologia. 30:128-134.
- Michaud HA et al. A crucial role for infected-cell/antibody immune complexes in the enhancement of endogenous antiviral immunity by short passive immunotherapy. (2010). PLoS Pathog. 6(6):e1000948.
- Le Saout C et al. IL-2 mediates CD4+ T cell help in the breakdown of memory-like CD8+ T cell tolerance under lymphopenic conditions.(2010). PLoS One. 5(9):e12659.
- Gros L et al. Endogenous cytotoxic T-cell response contributes to the long-term antiretroviral protection induced by a short period of antibody-based immunotherapy of neonatally infected mice. (2008). J Virol. 82:1339-49.
- Garaude J et al. Impaired anti-leukemic immune response in PKCtheta-deficient mice. (2008). Mol. Immunol. 45:3463-9.
- LeSaout C et al. Memory-like CD8+ and CD4+ T cells cooperate to break peripheral tolerance under lymphopenic conditions. (2008). Proc Natl Acad Sci U S A. 105:19414-9.
tel: 04 99 63 61 23
adress: INSERM U844, Hôpital Saint Eloi, bat INM, 80 rue Augustin Fliche, BP-74703, 34091 MONTPELLIER - Cedex 5, FRANCE
HERNANDEZ Javier (CR1/Inserm)
ESPINOSA Gabriel (PhD student/MESR)
BOUOUD Haifa (PhD student/Tunisia Gov.)
CD8+ T cell
CD4+ T cell
Type 1 diabetes