Dichotomous Expression of TNF Superfamily Ligands on Antigen-Presenting Cells Controls Post-priming Anti-viral CD4+ T Cell Immunity

Publication date: Available online 14 November 2017
Source:Immunity
Author(s): Yu-Han Chang, Kuan Chung Wang, Kuan-Lun Chu, Derek L. Clouthier, Anh T. Tran, Miguel S. Torres Perez, Angela C. Zhou, Ali A. Abdul-Sater, Tania H. Watts
T cell antigen-presenting cell (APC) interactions early during chronic viral infection are crucial for determining viral set point and disease outcome, but how and when different APC subtypes contribute to these outcomes is unclear. The TNF receptor superfamily (TNFRSF) member GITR is important for CD4⁺ T cell accumulation and control of chronic lymphocytic choriomeningitis virus (LCMV). We found that type I interferon (IFN-I) induced TNFSF ligands GITRL, 4-1BBL, OX40L, and CD70 predominantly on monocyte-derived APCs and CD80 and CD86 predominantly on classical dendritic cells (cDCs). Mice with hypofunctional GITRL in Lyz2⁺ cells had decreased LCMV-specific CD4⁺ T cell accumulation and increased viral load. GITR signals in CD4⁺ T cells occurred after priming to upregulate OX40, CD25, and chemokine receptor CX3CR1. Thus IFN-I (signal 3) induced a post-priming checkpoint (signal 4) for CD4⁺ T cell accumulation, revealing a division of labor between cDCs and monocyte-derived APCs in regulating T cell expansion.

Graphical abstract

Teaser

T cell-APC interactions modulate outcomes in chronic viral infections, but the division of labor between APC subtypes is unclear. Chang et al. reveal a dichotomy in costimulatory molecule expression whereby CD80 and CD86 are expressed mainly on classical DCs, and monocyte-derived APCs provide TNF family ligands for the post-priming accumulation of CD4⁺ T cells.


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