CD4 CTL, a Cytotoxic Subset of CD4+ T Cells, Their Differentiation and Function

Abstract

CD4+ T cells with cytotoxic activity (CD4 CTL) have been observed in various immune responses. These cells are characterized by their ability to secrete granzyme B and perforin and to kill the target cells in an MHC class II-restricted fashion. Although CD4 CTLs were once thought to be an in vitro artifact associated with long-term culturing, they have since been identified in vivo and shown to play important roles in antiviral and antitumor immunity, as well as in inflammation. Functional characterization of CD4 CTL suggests their potential significance for therapeutic purposes. However, in order to develop effective CD4 CTL therapy it is necessary to understand the differentiation and generation of these cells. Although the mechanisms regulating development of various CD4+ Th subsets have been clarified in terms of the cytokine and transcription factor requirement, the CD4 CTL differentiation mechanism remains elusive. These cells are thought to be most closely related to Th1 cells secreting IFNγ and regulated by eomesodermin and/or T-bet transcription factors for their differentiation. However, our studies and those of others have identified CD4 CTLs within other CD4+ T cell subsets, including naïve T cells. We have identified class I-restricted T cell-associated molecule as a marker of CD4 CTL and, by using this marker, we detected a subset of naïve T cells that have the potential to differentiate into CD4 CTL. CD4 CTL develops at sites of infections as well as inflammation. In this review, we summarize recent findings about the generation of CD4 CTL and propose a model with several differentiation pathways.

Deletion of the RNA regulator HuR in tumor‐associated microglia and macrophages stimulates anti‐tumor immunity and attenuates glioma growth

“…This is particularly relevant to GB since glioma‐associated TAMs generally have suppressed MHCII expression (Qian et al, ; Schartner et al, ). Interestingly, glioma cells in HuR KO tumors showed higher MHCII expression (Figure S3) which can facilitate antigen presentation and make them targets of CD4+ cytotoxic effector cells (Accolla et al, ; Takeuchi & Saito, ; Thibodeau, Bourgeois‐Daigneault, & Lapointe, ). Regardless of the source, MHCII molecules within tumors are key to triggering anti‐tumor immune responses (Accolla et al, ).…”

“…The graph below shows the mean densitometric values (±SEM) for the bands expressed as area under the curve (AUC). *p < .05; **p < .005; ***p < .0001 Takeuchi & Saito, 2017;Thibodeau, Bourgeois-Daigneault, & Lapointe, 2012). Regardless of the source, MHCII molecules within tumors are key to triggering anti-tumor immune responses (Accolla et al, 2014).…”

Pathogenic Th1 responses in CHIKV‐induced inflammation and their modulation upon Plasmodium parasites co‐infection

“…The contribution of IFNγ to CHIKV‐induced inflammation remains unclear, however, recent studies have suggested that CD4 + T cells might mediate CHIKV arthritic disease through the secretion of proteins other than IFNγ. RNA‐Seq analysis of CHIKV‐infected mouse footpads at the peak of swelling revealed highly induction of Granzyme A, a serine protease produced by NK cells, CD8 + T cells, and Th1 CD4 + T cells . Furthermore, deficiency of Granzyme A (GzmA −/− ) or treatment with Serpinb6b—a Granzyme A inhibitor—in mice abolished CHIKV‐induced joint swelling without affecting viremia.…”

Novel mechanism and biomarker of chronic progressive multiple sclerosis

“…Recent studies have shown that Th cells with a similar Eomes-expressing phenotype are generated under chronic inflammatory conditions associated with chronic viral infection, such as cytomegalovirus and human immunodeficiency virus 1, or can be induced within tumor microenvironments by immunomodulation. [73][74][75] Therefore, the developmental processes of Eomes+ Th cells in the CNS under chronic inflammation will provide other therapeutic means for preventing transition of the disease from RR-MS to SP-MS ( Fig. 3).…”