Modulatión of cd8+cytotoxic t cell immune responses against tumors by variable interactión kinetics between thet cell receptor and its ligand, the pmhc complex

Abstract

The immune system has an important role in recognizing and eliminating a huge number of foreign antigenic molecules potentially harmful to the organism, such as pathogens andmalignant cells. One of the cell types that contribute to this process are the effector CD8+cytotoxic T lymphocytes (CTL). CTL play a critica! role in the adaptive immunity, since theyare able to recognize and destroy viral/bacterial infected and tumor cells. CTLs may directly recognize tumoral or infected cells bearing antigens as peptides bound to MHC-1 molecules (pMHC) on their surface. Subsequently they mediate the killing of those cells by secretingcytokines and cytotoxic granules containing toxic proteins. such as granzymes. Because CTLs play a key role in successful anti-tumoral immune respone, it is important to dissect the molecular mechanisms underlying the activation and effector function of CD8+ T cellsin volved in these immune responses. CTL activation requires specitic recognition of pMHCcomplex on thc target cell surface by the T cell receptor (TCR). In addition, our group previously showed that the hal f-life of TCR/pMHC interaction modulates naYve CD8+ T cell activation. However, whether the effector function of CTLs can be regulated by the TCR/pMHC half-life remains unknown. In this thesis, we approached the question whether thet 1/2 of TCR/pMHC interaction can modulare the activation and function of naive and effectorCD8+ T cells in response to a tumor challenge. Our results suggest that efficient anti-tumor responses mcdiated by effector CD8+ T cells require an intermediate TCR/pMHC t1/2.Furthermore, the TCR/pMHC interaction half-life contributes to defining the nature of CTLanti-tumoral effector function. Thus, intermediare half-lives promote strong activation, eytokine secretion, expression of cytotoxic molecules efficient polarization of T cell lytic-machinery and subsequent release of toxic granules by CTLs, leading to the killing of tumor.