Non-cytotoxic functions of CD8 T cells: “repentance of a serial killer”

Abstract

Cytotoxic CD8 T cells (CTLs) are classically described as the “serial killers” of the immune system, where they play a pivotal role in protective immunity against a wide spectrum of pathogens and tumors. Ironically, they are critical drivers of transplant rejection and autoimmune diseases, a scenario very similar to the famous novel “The strange case of Dr. Jekyll and Mr. Hyde”. Until recently, it has not been well-appreciated whether CTLs can also acquire non-cytotoxic functions in health and disease. Several investigations into this question revealed their non-cytotoxic functions through interactions with various immune and non-immune cells. In this review, we will establish a new classification for CD8 T cell functions including cytotoxic and non-cytotoxic. Further, we will discuss this novel concept and speculate on how these functions could contribute to homeostasis of the immune system as well as immunological responses in transplantation, cancer, and autoimmune diseases.

CD8 T cells are dispensable for experimental autoimmune prostatitis induction and chronic pelvic pain development

“…An increasing body of evidence indicates that CD8 T cells play pivotal roles in the initiation, progression, pathogenesis, and protection for autoimmune diseases ( 75 , 76 ). In that regard, it is noteworthy to highlight that CD8 T cells can exert not only direct cytotoxic effects but also a myriad of actions, including indirect cytotoxicity, as well as direct and indirect non-cytotoxic functions via crosstalk with other immune and non-immune cells ( 35 ). These actions include the recruitment of other immune cells to inflammation sites, the activation of NK cells and dendritic cells to ensure antigen presentation and the induction of effector innate and adaptive immunity (mainly in an IFNγ dependent manner), the help to B cells to support antibody production, immunoregulation, and the induction of tissue healing and regeneration ( 35 , 76 , 77 ).…”

“…In that regard, it is noteworthy to highlight that CD8 T cells can exert not only direct cytotoxic effects but also a myriad of actions, including indirect cytotoxicity, as well as direct and indirect non-cytotoxic functions via crosstalk with other immune and non-immune cells ( 35 ). These actions include the recruitment of other immune cells to inflammation sites, the activation of NK cells and dendritic cells to ensure antigen presentation and the induction of effector innate and adaptive immunity (mainly in an IFNγ dependent manner), the help to B cells to support antibody production, immunoregulation, and the induction of tissue healing and regeneration ( 35 , 76 , 77 ). Interestingly, memory CD8 T cells were shown to protect dendritic cells from the killing by effector cytotoxic T cells via the upregulation of an endogenous inhibitor of granzymes, thus enhancing antigen presentation and thereby augmenting the consequent induction of Th1 immune responses ( 78 ).…”

“…CD8 T lymphocytes are crucial for the elimination of tumor cells and intracellular pathogens, demonstrating functional plasticity and complexity ( 33 , 34 ). However, it is currently known that CD8 T cells play a plethora of functions, encompassing direct and indirect cytotoxic and non-cytotoxic actions ( 35 ). Upon activation in secondary lymphoid organs following antigen presentation, naïve CD8 T cells undergo rapid clonal expansion, resulting in large numbers of antigen-specific acute effector and memory CD8 T cells.…”

“…Most CD8 T cells found in peripheral tissues are genuine T RM , which establish particular niches in nearly every organ ( 40 ). Regarding that, in is interesting to highlight that CD8 T cells are commonly found infiltrating inflamed tissues in several autoimmune diseases ( 35 , 38 ). Interestingly, increased levels of CD8 T cells have been reported in semen from CPPS/CP patients ( 24 ).…”

Scm6A: A fast and low-cost method for quantifying m6A modifications at the single-cell level

“…To gain deeper insights into the role of m 6 A in biological progresses, it becomes imperative to discern transcriptome-wide m 6 A levels and sites within individual cells. For instance, the presence of a multitude of immune cell and T-cell subtypes [8][9][10][11] poses a formidable challenge, as current m 6 A detection methods designed for bulk cell populations fall short in characterizing m 6 A levels and sites at the single-cell level.…”