Activated mouse CD4 + Foxp3 - T cells facilitate melanoma metastasis via Qa-1-dependent suppression of NK-cell cytotoxicity Academic Article uri icon

Overview

MeSH Major

  • CD4-Positive T-Lymphocytes
  • Forkhead Transcription Factors
  • Histocompatibility Antigens Class I
  • Killer Cells, Natural
  • Neoplasm Metastasis

abstract

  • The regulatory activities of mouse CD4(+)Foxp3(+) T cells on various immune cells, including NK cells, have been well documented. Under some conditions, conventional CD4(+)Foxp3(-) T cells in the periphery are able to acquire inhibitory function on other T cells, but their roles in controlling innate immune cells are poorly defined. As a potential cellular therapy for cancer, ex vivo activated CD4(+)Foxp3(-) effector T cells are often infused back in vivo to suppress tumor growth and metastasis. Whether such activated T cells could affect NK-cell control of tumorigenesis is unclear. In the present study, we found that mitogen-activated CD4(+)Foxp3(-) T cells exhibited potent suppressor function on NK-cell proliferation and cytotoxicity in vitro, and notably facilitated B16 melanoma metastasis in vivo. Suppression of NK cells by activated CD4(+)Foxp3(-) T cells is cell-cell contact dependent and is mediated by Qa-1:NKG2A interaction, as administration of antibodies blocking either Qa-1 or NKG2A could completely reverse this suppression, and significantly inhibited otherwise facilitated melanoma metastasis. Moreover, activated CD4(+)Foxp3(-) cells from Qa-1 knockout mice completely lost the suppressor activity on NK cells, and failed to facilitate melanoma metastasis when transferred in vivo. Taken together, our findings indicate that innate anti-tumor response is counter regulated by the activation of adaptive immunity, a phenomenon we term as "activation-induced inhibition". Thus, the regulatory role of activated CD4(+)Foxp3(-) T cells in NK-cell activity must be taken into consideration in the future design of cancer therapies.

publication date

  • December 2012

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3515753

Digital Object Identifier (DOI)

  • 10.1038/cr.2012.128

PubMed ID

  • 22945357

Additional Document Info

start page

  • 1696

end page

  • 706

volume

  • 22

number

  • 12