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  • Review Article
  • Published:

Targeting co-stimulatory pathways: transplantation and autoimmunity

Nature Reviews Nephrology volume 10, pages 14–24 (2014)Cite this article

Subjects

Key Points

  • T-cell co-stimulatory signals, expressed either constitutively or upon activation, critically affect the magnitude and character of autoreactive or alloreactive T-cell responses

  • Targeting T-cell co-stimulation pathways to reduce pathological T-cell responses has met with therapeutic success in many instances, but challenges remain

  • Efficacy of co-stimulatory blockade with abatacept or belatacept could be further optimized to improve inhibition of alloreactive and autoreactive T-cell responses by leaving co-inhibitory signals intact

  • Clinical application of CD154 pathway blockade has, thus far, been limited, but novel reagents in development might allow for therapeutic manipulation of this pathway to achieve immunological tolerance

  • Several other T-cell co-stimulatory pathways also hold promise as therapeutic targets for the treatment of autoimmunity and transplant rejection

  • Understanding the interplay between individual co-stimulatory and co-inhibitory pathways will lead to rational and targeted therapeutic interventions to manipulate T-cell responses and improve clinical outcomes

Abstract

The myriad of co-stimulatory signals expressed, or induced, upon T-cell activation suggests that these signalling pathways shape the character and magnitude of the resulting autoreactive or alloreactive T-cell responses during autoimmunity or transplantation, respectively. Reducing pathological T-cell responses by targeting T-cell co-stimulatory pathways has met with therapeutic success in many instances, but challenges remain. In this Review, we discuss the T-cell co-stimulatory molecules that are known to have critical roles during T-cell activation, expansion, and differentiation. We also outline the functional importance of T-cell co-stimulatory molecules in transplantation, tolerance and autoimmunity, and we describe how therapeutic blockade of these pathways might be harnessed to manipulate the immune response to prevent or attenuate pathological immune responses. Ultimately, understanding the interplay between individual co-stimulatory and co-inhibitory pathways engaged during T-cell activation and differentiation will lead to rational and targeted therapeutic interventions to manipulate T-cell responses and improve clinical outcomes.

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Figure 1: Complexities of the CD28 co-stimulatory pathway.
Figure 2: Comparison of abatacept and belatacept with selective CD28 blockade, and implications for T-cell activation.
Figure 3: Co-stimulatory pathways that might modulate memory T-cell responses in transplantation and autoimmunity.

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Acknowledgements

M. L. Ford is supported by R01 AI073707 and R01 AI104699. A. B. Adams and T. C. Pearson are supported by U19 AI1051731. The authors acknowledge Scott M. Krummey, Emory University, for help with conceptualization and design of figures.

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  1. The Emory Transplant Center, Emory University, 101 Woodruff Circle, Woodruff Memorial Research Building Suite 5105, Atlanta, 30322, GA, USA

    Mandy L. Ford, Andrew B. Adams & Thomas C. Pearson

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Contributions

M. L. Ford researched the data for the article. T. C. Pearson and M. L. Ford provided substantial contribution to discussions of the content. T. C. Pearson and M. L. Ford contributed to writing the article. T. C. Pearson, M. L. Ford and A. B. Adams contributed substantially to reviewing and/or editing of the manuscript before submission.

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Correspondence to Thomas C. Pearson.

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Competing interests

Mandy L. Ford and Andrew B. Adams have received research grants from Bristol-Myers Squibb. Thomas C. Pearson has received research grants from Bristol-Myers Squibb and Astellas.

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Ford, M., Adams, A. & Pearson, T. Targeting co-stimulatory pathways: transplantation and autoimmunity. Nat Rev Nephrol 10, 14–24 (2014). https://doi.org/10.1038/nrneph.2013.183

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