IL-2 and antigen dose differentially regulate perforin- and FasL-mediated cytolytic activity in antigen specific CD4+ T cells

Abstract

CD4 T cell effectors can promote survival against lethal influenza virus via perforin mediated cytolytic mechanisms, however; our understanding of how naïve CD4 cells differentiate into class II restricted killers remains obscure. To address this, TCR Tg CD4 cells were activated in vitro and examined for their ability to lyse target cells. We found that cytokine polarized CD4 T cell effectors displayed cytolytic activity with the hierarchy Th0>Th1>Th2. Further, IL-4 inhibited the generation of cytotoxic CD4 cells. LPS stimulated B cells and bone marrow derived dendritic cells (BMDC) both induced potent cytolytic activity; however, IL-6, TGF-β, IL-10, IL-12 or TNF-α were not required for inducing cytolytic activity in CD4 effectors. Antigen dose had a marked effect on cytotoxicity: low concentrations of peptide induced more potent cytolytic activity than relatively high concentrations. At low peptide concentration, exogenous IL-2 was necessary to drive granzyme B (GrB) expression and perforin mediated lysis. Thus, low antigen dose and early activation signals via IL-2 direct the CD4 T cell response toward effectors with perforin mediated cytolytic potential. These data have implications for the design of vaccines that may induce cytolytic CD4 cells in vivo and improve cell-mediated immunity to viral and bacterial infections.

Preferential Expansion of Human Virus-Specific Multifunctional Central Memory T Cells by Partial Targeting of the IL-2 Receptor Signaling Pathway: The Key Role of CD4+ T Cells

“…Consistent with other studies, our results demonstrated that CD4 + T cells elicited antiviral lytic T cell response apart from helper mechanisms (35) that is essential for retaining long-term immune control (36,37). Cytolytic CD4 + T cells are important in many chronic infections, such as EBV, HIV, and HCMV (38). In addition, the CD4 + T cells elicited a profound response to NEWTinfected iDC.…”

CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results

“…It is worth noting that the in vitro cytotoxicity of the T-cell product for UPN-02, which consisted primarily of CD4 ϩ T cells, was equivalent to that of the other patients with CD8 ϩ -predominant products. Robust cytolytic activity can be acquired by CD4 ϩ cells cultured in vitro with IL-2 44 and has been observed with ex vivo cultured CD4 ϩ CAR T cells in clinical trials as well. 2 As with our previous study, we found no evidence of cellular or humoral immune responses against the infused cells.…”

Cytokine-Dependent Induction of CD4+T cells with Cytotoxic Potential during Influenza Virus Infection

“…Previous studies had demonstrated that effector CD4 ؉ T cells can directly kill target cells by employing the cytolytic molecules Gzmb and perforin (13,16). We examined the expression of Gzmb in CD4 ؉ T cells during influenza A/PR8 virus infection.…”

“…Thus, understanding the cellular and molecular mechanisms regulating the development of these cells is of considerable significance with respect to viral infections, cancer, and autoimmunity. Currently, interleukin-2 (IL-2) signaling, low antigen dose, as well as OX40 and 41BB stimulation (13)(14)(15), have been suggested to promote the development of CD4 ؉ T cells with cytotoxic potential. However, the physiological signals in vivo and the downstream signaling pathways, as well as the underlying transcription factors regulating the development of these CD4 ϩ T cells remain undefined.…”