Research ArticleIMMUNOTHERAPY

CTLA-4–mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells

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Science Immunology  31 May 2019:
Vol. 4, Issue 35, eaaw0902
DOI: 10.1126/sciimmunol.aaw0902

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Tempering dendritic cell activation

Although checkpoint blockade targeting cytotoxic T lymphocyte associated protein 4 (CTLA-4) and programed cell death 1 (PD-1) have changed the landscape of cancer therapeutics, much remains to be learned about the biology of these molecules. CTLA-4 that is expressed on T cells has been shown to capture costimulatory molecules CD80 and CD86 from antigen-presenting cells by transendocytosis to inhibit CD28-mediated costimulation of T cell activation. Here, Ovcinnikovs et al. report that Tregs outperform conventional T cells in their ability to transendocytose CD80 and CD86 and that migratory dendritic cells are the main population targeted by Treg-expressed CTLA-4 in vivo. The study reveals a greater appreciation as to why CTLA-4 expressed on Tregs is so central in maintaining immune homeostasis.

Abstract

CTLA-4 is a critical negative regulator of the immune system and a major target for immunotherapy. However, precisely how it functions in vivo to maintain immune homeostasis is not clear. As a highly endocytic molecule, CTLA-4 can capture costimulatory ligands from opposing cells by a process of transendocytosis (TE). By restricting costimulatory ligand expression in this manner, CTLA-4 controls the CD28-dependent activation of T cells. Regulatory T cells (Tregs) constitutively express CTLA-4 at high levels and, in its absence, show defects in TE and suppressive function. Activated conventional T cells (Tconv) are also capable of CTLA-4–dependent TE; however, the relative use of this mechanism by Tregs and Tconv in vivo remains unclear. Here, we set out to characterize both the perpetrators and cellular targets of CTLA-4 TE in vivo. We found that Tregs showed constitutive cell surface recruitment of CTLA-4 ex vivo and performed TE rapidly after TCR stimulation. Tregs outperformed activated Tconv at TE in vivo, and expression of ICOS marked Tregs with this capability. Using TCR transgenic Tregs that recognize a protein expressed in the pancreas, we showed that the presentation of tissue-derived self-antigen could trigger Tregs to capture costimulatory ligands in vivo. Last, we identified migratory dendritic cells (DCs) as the major target for Treg-based CTLA-4–dependent regulation in the steady state. These data support a model in which CTLA-4 expressed on Tregs dynamically regulates the phenotype of DCs trafficking to lymph nodes from peripheral tissues in an antigen-dependent manner.

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