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

Abstract

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.

GITRL on inflammatory antigen presenting cells in the lung parenchyma provides signal 4 for T-cell accumulation and tissue-resident memory T-cell formation

“…In the chronic LCMV clone 13 infection model, GITR is mainly required on CD4 T cells to provide a post-priming checkpoint for CD4 accumulation and shows only indirect effects on CD8 T cells. 7,14 In contrast, in a T-cell adoptive transfer model of influenza infection, GITR was shown to mainly affect CD8 T-cell responses, with critical effects on viral control. 13 However, the role of GITR in the endogenous T cell responses to influenza virus, and when and where these signals take place are incompletely defined.…”

“…3,4 The initial activation of T cells requires an antigen bound to MHC (signal 1), a costimulatory signal through CD28 (signal 2) 5 as well as cytokines (signal 3). 6 Although these signals are important in initiating T-cell responses, additional post-priming signals from tumor necrosis factor receptor (TNFR) superfamily members play critical roles in controlling the duration of the T-cell responses, [7][8][9][10][11][12] referred to as signal 4. 7 Glucocorticoid-induced TNFR-related protein (GITR, TNFRSF18, or CD357), a costimulatory member of the TNFR superfamily plays an important role in the control of viral infections, including influenza virus and LCMV Clone 13.…”

“…6 Although these signals are important in initiating T-cell responses, additional post-priming signals from tumor necrosis factor receptor (TNFR) superfamily members play critical roles in controlling the duration of the T-cell responses, [7][8][9][10][11][12] referred to as signal 4. 7 Glucocorticoid-induced TNFR-related protein (GITR, TNFRSF18, or CD357), a costimulatory member of the TNFR superfamily plays an important role in the control of viral infections, including influenza virus and LCMV Clone 13. 7,[13][14][15] GITR is constitutively expressed at low levels on resting T cells and at high levels on CD4 + CD25 + regulatory T cells (Treg), 16,17 and is rapidly upregulated on CD4 and CD8 effector T cells upon activation.…”

“…7 Glucocorticoid-induced TNFR-related protein (GITR, TNFRSF18, or CD357), a costimulatory member of the TNFR superfamily plays an important role in the control of viral infections, including influenza virus and LCMV Clone 13. 7,[13][14][15] GITR is constitutively expressed at low levels on resting T cells and at high levels on CD4 + CD25 + regulatory T cells (Treg), 16,17 and is rapidly upregulated on CD4 and CD8 effector T cells upon activation. 16,17 GITR is also detected on other immune cell types such as B cells, NK cells, and macrophages.…”

“…18 GITR ligand (GITRL) is mainly expressed on antigen presenting cells (APCs) and endothelial cells, 19 with monocyte-derived inflammatory APCs showing the highest level of expression during chronic LCMV infection. 7 The role of GITR during viral infection appears context dependent. In the chronic LCMV clone 13 infection model, GITR is mainly required on CD4 T cells to provide a post-priming checkpoint for CD4 accumulation and shows only indirect effects on CD8 T cells.…”