Fernando Macian-Juan

Overview

The antigen receptors of T 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.

Two of the major of the mechanisms responsible for peripheral T cell tolerance are anergy, an intracellular process in which antigen receptors become uncoupled from their downstream signaling pathways, and regulatory T cells, a population of T cells with the ability to suppress activation of other T cells as well as B cells and dendritic cells. The biochemical pathways that cause inhibition of T cell responses in anergic or suppressed T cells are poorly understood. One of the goals of our lab is to study the molecular mechanisms responsible for the induction of tolerance in T cells. In T lymphocytes, integration of Ca2+ and other signaling pathways leads to productive activation, while unopposed Ca2+ signaling is associated with establishment of a tolerant state. A major consequence of Ca2+ mobilization is activation of members of the NFAT family of transcription factors. We have shown that NFAT1 plays a central role in tolerance induction in T cells. Using in vitro and in vivo mouse models, we have shown that tolerant T cells express a novel set of NFAT-dependent genes, distinct from those characteristics of a productive immune response that cause interference with signaling pathways coupled to antigen receptors, protein degradation and transcriptional modulation. We are currently characterizing the underlying molecular mechanisms involved in the establishment of T cell tolerance and identifying their molecular targets. We are also developing tools to modulate T cells tolerance to treat autoimmune disease or potentiate immune responses against cancer cells.

The immune system undergoes age-associated changes. Immunosenescence can be defined as the age-dependent decline in immune function which is responsible for the diminished ability to respond to infections, the lack of success of vaccination protocols and the increased incidence of autoimmune disease and cancer in the elderly. Degradation of proteins in the lysosomes via autophagy plays a key role in maintaining proper cell homeostasis, by reducing the accumulation of damaged proteins and recycling amino acids for new protein synthesis. Evidence suggests that decreased autophagic activity in old organism may be responsible for the deterioration of cell functions with age. We aim to determine how autophagy regulates T cell function, and how the age-dependent dysregulation of this process may account, at least in part, for the defective T cell function during aging.
 

Lab Members

Rachel Ames
Predoctoral Fellow
rachel.ames@phd.einsteinmed.org
718.430.2654

Sanmay Bandyopadhyay, PhD
Associate
sanmay.bandyopadhyay@einsteinmed.org
718.430.2654

Yair Botbol, PhD
Research Fellow
yair.botbol@einsteinmed.org
Forcheimer, Rm. 510
718.430.8086/2050

Ignacio Guerrero Ros
Predoctoral Fellow
ignacio.guerreroros@phd.einsteinmed.org
718.430.2654

Cara Reynolds 

Selected Publications

Shin D, Jordan A, Thomas RM, Bandyopadhyay S, de Zoeten EF, Wells AD and Macian F. (2014) NFAT-dependent transcriptional mechanisms regulate suppression of CD4+ T cells by Tregs. EMBO Rep (In press).

Bandhyopadhyay S, Valdor R, Macian F. (2014) Interferon gamma expression is epigenetically silenced by Tle4 in anergic T cells. Mol Cell Biol. 34:233-45.

Baine I, Basu S, Macian F. (2013) Helios induces epigenetic silencing of Il2 gene expression in natural regulatory T cells. J Immunol. 190:1008-16.

Abe, B.T., Shin, D.S., Mocholi, E., Macian, F. (2012) NFAT1 supports tumor-induced anergy of CD4+ T cells. Cancer Res. 72:4642-51.

Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM, Macian F. (2010) Macroautophagy regulates energy metabolism during effector T cell activation. J Immunol, 185:7349.

Soto-Nieves N, Puga I, Abe B, Bandyopadhyay S, Baine I, Rao A, Macian F. (2009) NFAT dimers regulate the expression of anergy-inducing genes in T cells. J Exp Med, 206:867.
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.

Bandyopadhyay S, Duré 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.