Fernando Macian-Juan, M.D., Ph.D.
The antigen receptors of T and B cells recognize not only antigens derived from pathogenic cells and organisms, but also self-antigens expressed on the body's own tissues. In healthy individuals, self-antigens do not elicit a significant immune response. Self-reactive lymphocytes are clonally eliminated during development and cells that survive this process are rendered tolerant in the periphery.
One of the mechanisms responsible for peripheral lymphocyte tolerance is anergyinduction, an intracellular process in which antigen receptors become un-coupled from their downstream signaling pathways. Anergic lymphocytes remain in a state of non-responsiveness that prevents harmful responses to self-tissues. The biochemical pathways that lead to anergy rather than full activation are still not completely understood. The goal of our lab is to study the molecular mechanisms responsible for the induction of tolerance in T cells. Combined activation of antigen and costimulatory receptors leads to full activation of all T cell receptor-coupled signaling pathways and culminates in a productive immune response. In contrast, tolerance is evoked by unbalanced stimulation of these receptors.
We have shown that NFAT proteins play a central role in tolerance induction in T cells. Using both ex-vivo and mice models, we have shown that tolerant T cells express a novel set of anergy-associated genes, distinct from those characteristics of a productive immune response. The expression of those genes is NFAT-dependent and does not seem to require AP-1 cooperation but instead depend on transcriptional complexes formed by NFAT dimers.
Thus, a single transcription factor, NFAT, regulates two contrasting aspects of T cell function, mediating non-overlapping genetic programs of productive activation or anergy depending on the availability of specific transcriptional partners.
This model predicts that blockade of the NFAT–AP1 interaction should prevent T-cell activation and induce a long-lasting state of tolerance. This is a key goal of organ transplantation that current regimes of immunosuppression fail to achieve. Furthermore, the inhibition of NFAT dimer interactions may prevent anergy induction and overcome on of the possible mechanisms responsible for tumor immune evasion.
The analysis of the specific genes activated in anergic T cells supports the existence of distinct mechanisms of tolerance induction in lymphocytes, including interference with signaling pathways coupled to antigen receptors, protein degradation and transcriptional modulation. We are currently studying the role of these processes in peripheral T cell tolerance, characterizing the underlying molecular mechanisms and identifying their molecular targets. Furthermore we are also investigating how these mechanisms may be involved in the regulatory T cell-mediated suppression of the activity of effector T helper cells.
Cell homeostasis requires of a regulated balance between synthesis and degradation of different cellular components. Autophagy, a catabolic pathway for the delivery and degradation in lysosomes of intracellular components, is one of the major systems involved in cellular quality control. Three different types of autophagy have been described in mammalian cells that differ in their regulation, substrate specificity and mechansim of delivery of the cargo into the lysosome. Dysregulation of autophagy with age has been described in many cells and has been proposed to be one of the causes of altered function of different organs and tissues in the elderly and of the development of age-related pathologies. We are currently characterizing the role of different forms of autophagy in T cells and analyzing the consequences of altered autophagic activity in aged T cells as a mechanism to explain the diminished T cell function that characterizes immunosenscence.
Valdor R, Mocholi E, Botbol Y, Guerrero-Ros I, Dinesh C, Koga H, Gravekamp C, Cuervo AM, Macian F (2014) Chaperone mediated autophagy regulates TCR signaling through targeted degradation of Rcan1 and Itch. Nat Immunol 15:1046-54
Shin DS, Jordan A, Basu S, Thomas RM, Wells AD, Macian F (2014) NFAT-dependent transcriptional mechanisms regulate suppression of effector CD4+ T cell activation by regulatory T cells. EMBO Rep, 15:991-9
Bandhyopadhyay S, Valdor R, Macian F (2014) Interferon gamma expression is epigenetically silenced by Tle4 in anergic T cells. Mol Cel Biol. 24:233-45
Baine I, Basu S, Ames R, Sellers RS, Macian F (2013) Helios induces epigenetic silencing of Il2 gene expression in natural regulatory T cells. J Immunol. 190:1008-16
Abe BT, Shin DS, Mocholi, E, Macian F (2012) NFAT1 supports tumor-induced anergy of CD4+ T cells. Cancer Res 72:4642-51
Valdor R, Macian F (2012) Autophagy and the regulation of the immune response. Pharmacol Res. 66:475-83
Bandyopadhyay S, Montagna C, Macian F (2012) Silencing of the Il2 gene transcription is regulated by epigenetic changes in anergic T cells. Eur J Immunol. 42:2471-83
Hubbard VM., Patel B., Cuervo AM and Macian F (2010) Selective activation of macroautophagy provides a key source of energy during effector T cell activation. J Immunol. 13:7349-57
Soto-Nieves N, Puga I, Abe B, Bandyopadhyay S, Baine I, Rao A, Macian F (2009) Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance. J Exp Med. 206:867-76
Duré M, Macian F (2009) IL-2 signaling prevents T cell anergy by inhibiting the expression of anergy inducing genes. Mol Immunol. 46:999-1006
Puga I, Rao A, Macian F (2008) Targeted cleavage of GADS and Vav1 by Caspase 3 inhibits T cell receptor signaling in anergic T cells Immunity. 29:193-204
Bandhyopadhyay S, Dure M, Paroder M, Soto-Nieves N, Puga I, Macian F (2007) Interleukin 2 gene transcription is regulated by Ikaros-induced changes in histone acetylation in anergic T cells. Blood. 109:2878-86
Macian F (2005) NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 5:472-84
T cell; NFAT; Anergy; Regulatory T cell; Tolerance; Autophagy
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