Downregulation of Innate and Acquired Antitumor Immunity by Bystander gamma delta and alpha beta T Lymphocytes with Th2 or Tr1 Cytokine Profiles

Abstract

It has been thought that natural killer (NK) cells appearing early in tumor lesions play a pivotal role in the innate immunity against tumor cells. Although NK cells serve as the first tumoricidal effector cells, they subsequently promote a shift in effectors from themselves to tumor-specific cytotoxic T lymphocytes (CTLs) that mediate the acquired immunity. The mechanism of this shift has not been fully elucidated, however, NK cell-derived T helper (Th) 1 cytokines such as interferon (IFN)-gamma seem to play a key role. Another NK-lineage, termed natural killer T (NK T) cells, may also participate in the innate period when they acquire the ability to secrete Th1 cytokines. Interleukin-4 (IL-4) and IL-10, belonging to Th2, and transforming growth factor-beta (TGF-beta), belonging to T regulatory (Tr) 1 cytokines, are known to suppress the development of NK, NK T cells, as well as CTLs and to block Th0 cell differentiation to Th1 cells, suggesting that tumor cells can evade the innate and acquired immunity by virtue of cells producing these inhibitory cytokines. In early tumor lesions of murine B16 melanoma, gammadelta T and alphabeta intermediate (int) T cells that co-infiltrate with NK and NK T cells can produce Th2 cytokines and inhibit the innate immunity. In MM2 mammary tumor-bearing mice, gammadelta T cells appearing both lesionally and systemically secrete Tr1-type cytokines and depress the acquired immunity. These Th2- or Tr1-type gammadelta T and alphabeta(int) T cells downregulate the tumoricidal cells by means of both their secreted cytokines and express major histocompatibility complex (MHC) class I molecules.

Effect of mindfulness based stress reduction on immune function, quality of life and coping in women newly diagnosed with early stage breast cancer

“…The clinical significance of immune modulation during cancer is supported in several ways. High levels of NKCA in cancer patients correlate with a good prognosis (Gonzales, et al, 1998;Koda, et al, 1997;Liljefors, et al, 2003;Nakamura, et al, 2000;Seo and Tokura, 1999;Taketomi, et al, 1998). Impaired NKCA correlates with invasiveness of human malignancy (Levy, et al, 1984) and reduced NKCA is a significant prognostic indicator of lymphatic involvement, serosal invasion, lymph node metastatic disease and a poorer survival rate (Takeuchi, et al, 2001).…”

Adapting a transforming growth factor β–related tumor protection strategy to enhance antitumor immunity

“…23,48,54 Hodgkin cells also secrete the chemokine TARC, which specifically recruits IL-4-secreting Th2 cells, and a Th2 growth factor, IL-13. [55][56][57][58] Both favor the creation of a noncytotoxic Th2 environment. Although this is a daunting list of evasion mechanisms, their very profligacy argues that multiple defenses are required to protect the tumor cells from attack.…”

γδ T Cells Promote Anterior Chamber-Associated Immune Deviation and Immune Privilege through Their Production of IL-10

“…Other reports have suggested that the immunosuppressive function of ␥␦ T cells is mediated mainly by cytokines (42,45). Because ACAID is a Th2-like phenomenon with an immunosuppressive consequence, we hypothesized that ␥␦ T cells need to secrete Th2 cytokines (such as IL-10 and IL-4) for the generation of efferent Tregs and down-regulation of DTH.…”