ORCID

0000-0002-9521-1657

Date of Award

5-8-2024

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Classical dendritic cells (cDCs) are specialized antigen presenting cells that comprise distinct subsets distinguished by transcriptional developmental differences and in the types of immune responses they initiate. Classical type 1 dendritic cells (cDC1) are thought to perform antigen cross-presentation, which is required to prime CD8 T cells, whereas cDC2 have been suggested to be specialized for priming CD4 T cells. CD4 T cell help for CD8 T cell responses has been proposed to be mediated by CD40-dependent licensing of antigen-presenting cells. cDC1 have been suggested as the target of CD4 T cell help on the basis of in vitro analysis and intravital imaging during viral infection. However, despite extensive analysis, a requirement for cDC1 in mediating CD4 T cell help in vivo has not been directly established, and the downstream mechanism of CD40 help remains unclear. To evaluate the function of cDC1 in initiating CD4 and CD8 T cell responses in vivo, we generated a novel Xcr1-Cre mouse line that allows for inactivation of genes selectively in cDC1. We found that, in contrast to recent models, early priming of CD4+ T cells against tumor-derived antigens required cDC1 specifically for antigen presentation, as selective deletion of major histocompatibility class II (MHC II) molecules in cDC1 prevented early CD4 T cell priming. Deletion of either MHC II or CD40 in cDC1 impaired both tumor rejection and tumor-specific CD8 T cell priming, consistent with a role for cognate CD4 T cell interactions and CD40 signaling in cDC1 licensing. However, the precise mechanism by which CD40 signaling in cDC1 licenses the effective activation of tumor-specific CTL responses remained undefined. Therefore, we systematically identified CD40-induced genes in cDC1, including Cd70, Tnfsf9, Ptgs2, and Bcl2l1, and examined their contributions to anti-tumor immunity. We found that cDC1-specific inactivation of CD70 and COX-2, and global CD27 inactivation, only partially impaired tumor rejection or tumor-specific CD8 T-cell expansion. Loss of 4-1BB, alone or in Cd27-/- mice, did not further impair anti-tumor immunity. However, cDC1-specific CD40 inactivation reduced cDC1 mitochondrial transmembrane potential and increased caspase activation in tumor-draining lymph nodes, reducing migratory cDC1 numbers in vivo. Similar impairments occurred during in vitro antigen presentation by Cd40-/- cDC1 to CD8 T cells, which were reversed by re-expression of Bcl2l1. Thus, CD40 signaling acts as a control hub in cDC1, not only inducing co-stimulatory ligands for CD8 T cells, but also inducing Bcl2l1 that sustains cDC1 survival during priming of anti-tumor responses. These advances provide new insight into the cellular interactions and proteins involved in CD4 help for CD8 T cell anti-tumor responses.

Language

English (en)

Chair and Committee

Kenneth Murphy

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