During an immune response, activated antigen (Ag)-specific T cells condition dendritic cells (DCs) to enhance DC function and survival within the inflamed draining lymph node (LN). It has been difficult to ascertain the role of the tumor necrosis factor (TNF) superfamily member lymphotoxin-αβ (LTαβ) in this process because signaling through the LTβ-receptor (LTβR) controls multiple aspects of lymphoid tissue organization. To resolve this, we have used an in vivo system where the expression of TNF family ligands is manipulated only on the Ag-specific T cells that interact with and condition Ag-bearing DCs. We report that LTαβ is a critical participant required for optimal DC function, independent of its described role in maintaining lymphoid tissue organization. In the absence of LTαβ or CD40L on Ag-specific T cells, DC dysfunction could be rescued in vivo via CD40 or LTβR stimulation, respectively, suggesting that these two pathways cooperate for optimal DC conditioning.
The lymphotoxin (LT) pathway has been shown to be important in T cell responses and DC homeostasis/activation. LTαβ is a TNF family member upregulated on activated T cells and its receptor, LTβR, is constitutively expressed on DC. Elucidating the role of LTβR signaling in DC function is complicated by the expression of LTβR on both lymphoid stromal cells and DC. Here we have used two methods for inhibiting LTβR signaling. In the first we use an in vivo adoptive transfer system where the expression of the LTβR ligands is manipulated only on the Ag‐specific T cells that interact with and condition Ag‐bearing DC. Using this approach we demonstrate a novel requirement for the LTαβ for optimal DC conditioning during an immune response against protein antigen.In the second system, we have manipulated the expression of LTβR on DC using a mixed bone marrow chimera approach. Here we report a requirement for DC‐intrinsic LTβR signaling for the optimal upregulation of CD86. In addition, DC‐intrinsic LTβR signaling influences DC accumulation in the inflamed LN. Together these data identify a fundamental role for DC‐intrinsic LTβR signaling during T cell immune responses. Funding from CIHR (JLG and LSD) and MS Society of Canada (LSD) supported this research.
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