Abstract IA08: Mechanisms and signaling pathways involved in regulation of activating and inhibitory T cell responses
Authors: Boussiotis Vassiliki A. 
Published: May 2016

One of the most remarkable properties of the immune system is its ability to recognize, respond to, and eliminate foreign antigens while not reacting harmfully to that individual's own antigens and inducing autoimmunity. The specificity of T cell responses is controlled by the antigen-specific T cell receptor (TCR). However, full T cell activation is generally achieved only in the presence of additional receptor-ligand interactions. When these interactions take place at the same time as TCR engagement, they are referred to as costimulatory signals. Such costimulatory signals allow the T cells to enter the cell cycle and prepare for cell division. These signals also program T cells to produce IL-2 leading to survival and clonal expansion. It is well established that engagement of CD28 by its ligands B7-1 (CD80) or B7-2 (CD86) lowers the threshold for activation of T cells and provides key costimulatory signals to naive T cells. However, the T cell response is not a single event. T cells first recognize antigen-MHC on an antigen-presenting cell (APC) and, during the first few hours of activation, commit to expansion. This initial activation is usually dependent on CD28-B7 interaction. Subsequently, T cells differentiate into effector cells, which can interact with B cells in germinal centers and/or migrate out of the lymphoid organs and carry out their effector functions in the peripheral tissues. Although the majority of T effector cells are short-lived, some antigen-experienced cells remain as long-lived memory cells. T cells receive activation or survival signals at each stage of the response, including naive, effector, and memory stages. Members of the tumor necrosis factor (TNF) family are emerging as key mediators of survival in T cells subsequent to the initial effects of CD28-B7 interaction.

Pathways in the B7:CD28 family have key roles in regulating initiation activation of naïve T cells and in guiding their fate toward immunity or tolerance. This dual outcome is secondary to the fact that the B7 superfamily members not only provide critical positive second signals that promote and sustain T cell responses, but also contribute critical negative second signals. These negative signals function to limit, terminate, and/or attenuate T cell responses, and appear to be especially important for regulating T cell tolerance and autoimmunity. The B7-1/B7-2: CD28/CTLA-4 pathway is the best-characterized T cell costimulatory pathway and its dual specificity has been well established. CD28 delivers signals important for T cell activation and survival, whereas CTLA-4 inhibits T cell responses and regulates peripheral T cell tolerance. Two newer pathways in the B7:CD28 superfamily with significant role in disease conditions involve: ICOS (inducible costimulator) and ICOS ligand (also known as B7h, GL50, B7RP-1, LICOS, B7-H2); PD-1 receptor and its ligands, PD-L1 (also known as B7-H1) and PD-L2 (also known as B7-DC). Members of the B7: CD28 superfamily do not have enzymatic activity or specific enzymes associated with their cytoplasmic tails. As a consequence, they do not induce unique signaling events. However, these molecules have a key role in regulating the balance of TCR-mediated signals thereby allowing a distinct pattern of signaling events to be induced by co-stimulatory versus co-inhibitory receptors.

Receptors of the TNF family (TNFRs) are central to the function of CD4+ and CD8+ T cells. Among them, the biology of certain TNFR members including OX40 (also known as CD134 and TNFRSF4), 4-1BB (also known as CD137 and TNFRSF9), CD27 (also known as TNFRSF7), HVEM, CD30, and GITR have drawn significant attention due to their properties and their potential to be exploited for therapeutic benefit. The primary function of the TNF superfamily molecules is to regulate cell survival. Inhibition of TNFR interactions prevents the activation of signaling pathways downstream of the TNFRs, thereby minimizing the pro-inflammatory program that is initiated by these molecules and decreasing the pathology of autoimmune and inflammatory diseases. TNFRs not only positively regulate T-cell responses but also mediate crosstalk between T cells and other cell types. Manipulating these interactions can be appropriate in various conditions, including inflammation, autoimmunity and cancer. In contrast to the members of the B7:CD28 superfamily, signaling pathways activated downstream of the TNFRs are specific and well defined. Thus, not only targeting TNFRs themselves by using of blocking or agonistic antibodies but also targeting these downstream signaling pathways can be an effective way to modulate immune responses. The effects of these TNFR family members are functionally, temporally, or spatially segregated from those of CD28 family members and from each other. The sequential and transient regulation of T cell activation/survival signals by different costimulators may function to allow longevity of the response while maintaining tight control of T cell survival and preventing autoimmunity.

I will focus on the activity of these molecules in regulating the function of T cells and their crosstalk with other immune cells, and discuss how these molecules their signaling signatures and their interactions relate to inflammation, autoimmunity and cancer, diseases in which these molecular targets are promising candidates for therapy.

Citation Format: Vassiliki A. Boussiotis. Mechanisms and signaling pathways involved in regulation of activating and inhibitory T cell responses. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA08.