Farklı Aktivasyon Basamaklarına İlerletilen Yardımcı T Hücrelerinde Adezyon ve Migrasyon Mekanizmalarının İncelenmesi

Abstract

When different analog T lymphocyte profiles are examined in cancer and chronic infections, these cells can be divided into two subgroups with functional and dysfunctiononal characterization. Naive T lymphocytes which are stimulated by T cell receptor (TCR) signal and costimulation, go through activation process. In the co-culture model used in this thesis study, TCR signal and costimulation signals were provided through anti-CD3 antibody and monocytic cell line, as a result of these, continuous stimulation of helper T lymphocytes (Th) was achieved and functional and dysfunctional Th lymphocytes were obtained. Th lymphocytes of the co-culture where they are activated, proliferated, differentiated, acquired effector functions and formed pre-exhausted/memory Th lymphocyte populations in 0., 12., 24., 48., 72., 96., 120. and 144. hours were demonstrated by the analysis of phenotype, function, morphology, transcriptomics, adhesion and migration dynamics. It has been explained that the co-cultured naive CD4 + T lymphocytes differentiate into effector Th1 cells producing IFN-, TNF- and IL-2, and in the late stages of culture, these cells formed pre-exhausted/memory Th lymphocyte populations by their reduced cytokines production and proliferation capacities and increased inhibitor receptor expression on their surface. It has been determined that the pre-exhausted/memory Th1 lymphocytes reinvigorate their functionality with blockages of PD-1 and CTLA-4 receptors, and in particular, their adhesion and migration capacities increased under anti-PD-1 blockade. As a result, with the developed co-culture model, how Th1 cells are affected by the checkpoint blockade immunotherapy approach has been evaluated comprehensively and in detail.