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High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.

Publication ,  Journal Article
Krummey, SM; Cheeseman, JA; Conger, JA; Jang, PS; Mehta, AK; Kirk, AD; Larsen, CP; Ford, ML
Published in: Am J Transplant
March 2014

The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation,which led us to investigate the etiology of belatacept–resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectively enable protection against diverse classes of pathogens and can cross-react with allogeneicantigen and mediate graft rejection. T helper 17(Th17) cells are a pro-inflammatory CD4+ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1)and Th17 memory compartments contained a similar frequency of divided cells following allogeneic stimulation.Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of the coinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses but augmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renal transplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevated frequency of Th17 memory cells was associated with acute rejection during belatacept therapy. These data highlight important differences in costimulatory and coinhibitory requirements of CD4+ memory subsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications for immunomodulation strategies.

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Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

March 2014

Volume

14

Issue

3

Start / End Page

607 / 614

Location

United States

Related Subject Headings

  • Th17 Cells
  • Surgery
  • Prognosis
  • Middle Aged
  • Male
  • Lymphocyte Activation
  • Kidney Transplantation
  • Kidney Diseases
  • Immunosuppressive Agents
  • Immunologic Memory
 

Citation

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Krummey, S. M., Cheeseman, J. A., Conger, J. A., Jang, P. S., Mehta, A. K., Kirk, A. D., … Ford, M. L. (2014). High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. Am J Transplant, 14(3), 607–614. https://doi.org/10.1111/ajt.12600
Krummey, S. M., J. A. Cheeseman, J. A. Conger, P. S. Jang, A. K. Mehta, A. D. Kirk, C. P. Larsen, and M. L. Ford. “High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.Am J Transplant 14, no. 3 (March 2014): 607–14. https://doi.org/10.1111/ajt.12600.
Krummey SM, Cheeseman JA, Conger JA, Jang PS, Mehta AK, Kirk AD, et al. High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. Am J Transplant. 2014 Mar;14(3):607–14.
Krummey, S. M., et al. “High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept.Am J Transplant, vol. 14, no. 3, Mar. 2014, pp. 607–14. Pubmed, doi:10.1111/ajt.12600.
Krummey SM, Cheeseman JA, Conger JA, Jang PS, Mehta AK, Kirk AD, Larsen CP, Ford ML. High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. Am J Transplant. 2014 Mar;14(3):607–614.
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

March 2014

Volume

14

Issue

3

Start / End Page

607 / 614

Location

United States

Related Subject Headings

  • Th17 Cells
  • Surgery
  • Prognosis
  • Middle Aged
  • Male
  • Lymphocyte Activation
  • Kidney Transplantation
  • Kidney Diseases
  • Immunosuppressive Agents
  • Immunologic Memory