Autophagy Dysfunction and  Immunosenescence

Introduction
 » Goal
 » Specific Aims  

Subprojects

» Autophagy and T cell activation

» Autophagy and T cell tolerance

» Mechanisms of Immunosenescence

Members
Fernando Macian
Rut Valdor        Vanessa Hubbard     Ajana Jordan              Ian Baina      

Project 3 will investigate  the role that autophagy plays in the control of T cell responses and determine if the decrease in autophagic activity with age isinvolved in the immunosenescent phenotype.

Cellular homeostasis requires a careful balance between protein synthesis and protein degradation. Constant protein turnover is necessary not only to reduce the accumulation of damaged proteins in the cell, and to recycle amino acids for new protein synthesis, but it also allows for the modification of protein levels in response to extracellular signals. A major pathway involved in the degradation of long-lived proteins is autophagy, a catabolic process that delivers cytoplasmic material to the lysosomes for degradation. Three main types of autophagy have been described in mammalian cells: macroautophagy (MA), chaperone mediated autophagy (CMA) and microautophagy. Different mechanisms control the regulation of these three forms of autophagy and the targeting of their substrates to the lysosomes. These systems are critical for proper cell function, as their failure, as seen in several diseases, leads to the intracellular accumulation of abnormal proteins, defective regulation of many cellular processes and altered responses to stress.

Although the role of autophagy in many tissues and systems has been characterized, it is still not completely understood whether autophagy has a role in the regulation of the adaptive immune system and the processes regulated by autophagy and the mechanism that regulate of MA and CMA activity in T cells remain to be characterized.

The activity of MA and CMA has been shown to decrease with age. Our group has gathered evidence that indicates that aged CD4+ T cells cannot properly regulate autophagic activity in response to TCR engagement. We intend, thus, to characterize the functional consequences of this defect for T cell function in old organisms.

As with many other systems, the immune system in also affected by age. Immunosenescence is characterized by a decrease ability of immune cells to mount a productive response upon exposure to new antigens, accounting for the increased susceptibility of the elderly to infectious disease and for the poor responses to vaccination. Alterations of immune responses with age reflect defects in several cell types, although CD8+ and CD4+ T cells appear to be particularly affected . Although the total numbers of T cells do not seem to change in the elderly, there are clear differences in the T cell compartment between young and old individuals. These changes are a consequence of a diminished thymic output, due to the age-associated thymic involution, increased homeostatic division , life-long exposure to pathogens and, likely, aging of the bone marrow-derived T cell precursors. Old naïve and memory T cells, and even recent thymic emigrants in aged mice, respond poorly to antigen and show defects in many signaling pathways.Paradoxically, the risk of suffering several autoimmune diseases increases also with age. Peripheral T cell tolerance is maintained mainly through three different mechanisms: T cell anergy, regulatory T cells (Tregs) and peripheral deletion of self-reactive T cells. T cell anergy can be defined as a long-lasting status of unresponsiveness induced by suboptimal stimulation. Classical clonal anergy has been described following the two signal model as a consequence of T cells being stimulated through the TCR (signal 1) without engagement of costimulatory molecules (e.g. CD28, signal 2), as opposed to full T cell activation achieved when both signals are engaged. We have recently demonstrated that signaling through the TCR in the absence of costimulation results in an unbalanced activation of the Ca2+/Calcineurin pathway that induces NFAT dephosphorylation and activation in the absence of AP-1 activation. As a result of this unbalanced activation, an anergy-specific set of genes is expressed, which encode proteins necessary for the induction and likely the maintenance of the anergic status. Signals transmitted through the TCR are able to implement, thus, two opposite programs: activation and anergy. Age-associated defects in TCR-induced signaling may, thus, affect not only T cell activation but also T cell anergy.

Our goal is to elucidate the role that autophagy plays in the control of Th cell responses and determine if the decrease in autophagic activity with age is involved in the immunosenescent phenotype, characterized by decreased responses to foreign antigens and increased risk of autoimmunity.

Gaining new insights on the causes that lead to altered T cell function in the elderly, may not only offer new knowledge on the altered regulation of T cell activation and T cell tolerance with age but it may also set the basis for future therapeutic interventions.

Role of NFAT proteins in the regulation of T cell activation and T cell tolerance

Nuclear trasnlocation of NFAT in response to calcium signals in T cells

Autophagosome formation in activated T cells