MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4+ T cells in vivo

Thomas V Guy; Alexandra M Terry; Helen M McGuire; Elena Shklovskaya; Barbara Fazekas de St Groth

doi:10.1080/2162402X.2023.2290799

MHCII restriction demonstrates B cells have very limited capacity to activate tumour-specific CD4⁺ T cells in vivo

Oncoimmunology. 2023 Dec 10;13(1):2290799. doi: 10.1080/2162402X.2023.2290799. eCollection 2024.

Authors

Thomas V Guy^{1

2}, Alexandra M Terry^{1

3}, Helen M McGuire^{1

4}, Elena Shklovskaya^{1

5}, Barbara Fazekas de St Groth^{1

4}

Affiliations

¹ T cell Biology Program, Centenary Institute of Cancer Medicine and Cell Biology, Sydney, NSW, Australia.
² Pillai Labratory, Ragon Institute of MGH, Harvard and MIT, Boston, MA, USA.
³ Genmab, Utrecht, The Netherlands.
⁴ School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
⁵ Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.

Abstract

There has been growing interest in the role of B cells in antitumour immunity and potential use in adoptive cellular therapies. To date, the success of such therapies is limited. The intrinsic capacity of B cells to specifically activate tumour-specific CD4+ T cells in vivo via TCR-dependent interactions remains poorly defined. We have developed an in vivo tumour model that utilizes MHCII I-E restriction which limits antigen presentation to tumour-specific CD4 T cells to either tumour-specific B cells or host myeloid antigen presenting cells (APCs) in lymphopenic RAG-/-mice. We have previously shown that these naive tumour-specific CD4+ T cells can successfully eradicate established tumours in this model when activated by host APCs. When naïve tumour-specific B cells are the only source of I-E+ APC, very limited proliferation of naïve CD4+ T cells is observed, whereas host I-E+ APCs are potent T cell activators. B cells pre-activated with an anti-CD40 agonistic antibody in vivo support increased T cell proliferation, although far less than host APCs. CD4+ T cells that have already differentiated to an effector/central memory phenotype proliferate more readily in response to naïve B cells, although still 100-fold less than in response to host APCs. This study demonstrates that even in a significantly lymphopenic environment, myeloid APCs are the dominant primary activators of tumour-specific T cells, in contrast to the very limited capacity of tumour-specific B cells. This suggests that future anti-tumour therapies that incorporate activated B cells should also include mechanisms that activate host APCs.

Keywords: Antigen presentation; B cell; MHC restriction; T cell; tumour.

MeSH terms

Animals
Antigen-Presenting Cells* / physiology
B-Lymphocytes
CD4-Positive T-Lymphocytes
Lymphocyte Activation
Mice
Neoplasms*

Grants and funding

This work was supported by Australian National Health and Medical Research Council grants 1001020, 1012930 and 1051843 and a New South Wales Cancer Council grant RG 13-13. TVG was supported by scholarships from the Cancer Institute New South Wales, and B.F.deStG. by a fellowship from the National Health and Medical Research Council of Australia. All experiments were performed with the consent of the University of Sydney Animal Ethics Committee, or Sydney Local Health District Animal Welfare Committee.