Molecular basis of CD4⁺ T cell help for the cytotoxic T cell response

CD8⁺ T cells represent a subset of adaptive immune cells and have been the central focus of cancer immunotherapy. Their unique abilities to reach almost all body parts, recognize intracellular alterations in the context of ubiquitous MHC class I molecules and mediate target cell killing make them an ideal weapon against cancer. The activity of CD4⁺ T cells is required to initiate and sustain optimal CD8⁺ T cells responses, especially in the case of cancer. In my work, I have focused on the central role of these cells during early phases of the CD8⁺ T cell response. I have described novel molecular mechanisms by which both primary and memory CD8⁺ T cell responses are enhanced by CD4⁺ T cell help. I found that CD8⁺ T cells primed in the absence of CD4⁺ T-cell help expressed low levels of numerous effector molecules. CD4⁺ T-cell help results in downregulation of multiple inhibitory receptors by CD8⁺ T cells and in turn leads to a better tumor control. Furthermore, I found that “helped” CD8⁺ T cells upregulated multiple chemokine receptors and therefore were able to traffic more efficiently to the tumor. Once in the tumor they had increased ability to infiltrate through the tumor tissue due to upregulation of enzymes degrading the components of extracellular matrix. Moreover, I have examined the role of CD4⁺ T cell help in the response to immunomodulatory antibodies in the context of anti-cancer vaccination, highlighting the importance of ‘help’ for optimal anti-tumor immunity.