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Paradoxical inhibition of T-cell function in response to CTLA-4 blockade; heterogeneity within the human T-cell population

Nature Medicine volume 6, pages 211–214 (2000)Cite this article

Abstract

T-cell co-stimulation delivered by the molecules B7-1 or B7-2 through CD28 has a positive effect on T-cell activation1, whereas engagement of cytotoxic T-lymphocyte antigen 4 (CTLA-4) by these molecules inhibits activation2. In vivo administration to mice of blocking monoclonal antibodies or Fab fragments against CTLA-4 can augment antigen-specific T-cell responses3,4 and, thus, therapy with monoclonal antibody against CTLA-4 has potential applications for tumor therapy and enhancement of vaccine immunization5,6,7. The effects of B7-1 and B7-2 co-stimulation through CD28 depend on the strength of the signal delivered through the T-cell receptor (TCR)8,9 and the activation state of T cells during activation10,11. Thus, we sought to determine whether these factors similarly influence the effect of B7-mediated signals delivered through CTLA-4 during T-cell activation. Using freshly isolated human T cells and Fab fragments of a monoclonal antibody against CTLA-4, we demonstrate here that CTLA-4 blockade can enhance or inhibit the clonal expansion of different T cells that respond to the same antigen, depending on both the T-cell activation state and the strength of the T-cell receptor signal delivered during T-cell stimulation. Thus, for whole T-cell populations, blocking a negative signal may paradoxically inhibit immune responses. These results provide a theoretical framework for clinical trials in which co-stimulatory signals are manipulated in an attempt to modulate the immune response in human disease.

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Figure 1: The effect of CTLA-4 blockade on cytokine secretion depends on the strength of signal through the TCR.
Figure 2: CTLA-4 blockade enhances Th2 cytokine secretion from PBMCs stimulated at high antigen concentrations.
Figure 3: CTLA-4 blockade differentially affects the expansion of T cells with identical specificities.

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Acknowledgements

We thank V. Kuchroo and members of his laboratory for discussions. This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases grants 1PO1A139671-03, RO1DK52127, RO1NS2424710A2 (D.A.H.), and a grant from Genetics Institute (D.A.H.). A.B. was supported by a Multiple Sclerosis Society of Canada Research Fellowship and by the Clinical Investigator Training Program: Harvard/Massachusetts Institute of Technology Health Sciences and Technology–Beth Israel Deaconess Medical Center, in collaboration with Pfizer.

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Authors and Affiliations

  1. Division of Medical Sciences, Committee on Immunology, Harvard Medical School, Boston, 02115, Massachusetts

    David E. Anderson & David A. Hafler

  2. Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, HIM 780, Boston, 02115, Massachusetts

    David E. Anderson, Katarzyna D. Bieganowska, Amit Bar-Or, Enedina M.L. Oliveira & David A. Hafler

  3. Genetics Institute, Cambridge, 02140, Massachusetts

    Beatriz Carreno & Mary Collins

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Anderson, D., Bieganowska, K., Bar-Or, A. et al. Paradoxical inhibition of T-cell function in response to CTLA-4 blockade; heterogeneity within the human T-cell population. Nat Med 6, 211–214 (2000). https://doi.org/10.1038/72323

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