In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 6 ( 2023-6-22), p. e1011455-
Abstract:
XIAP is an endogenous inhibitor of cell death and inactivating mutations of XIAP are responsible for X-linked lymphoproliferative disease (XLP-2) and primary immunodeficiency, but the mechanism(s) behind these contradictory outcomes have been unclear. We report that during infection of macrophages and dendritic cells with various intracellular bacteria, XIAP restricts cell death and secretion of IL-1β but promotes increased activation of NFκB and JNK which results in elevated secretion of IL-6 and IL-10. Poor secretion of IL-6 by Xiap -deficient antigen presenting cells leads to poor expansion of recently activated CD8 T cells during the priming phase of the response. On the other hand, Xiap -deficient CD8 T cells displayed increased proliferation and effector function during the priming phase but underwent enhanced contraction subsequently. Xiap -deficient CD8 T cells underwent skewed differentiation towards short lived effectors which resulted in poor generation of memory. Consequently Xiap -deficient CD8 T cells failed to provide effective control of bacterial infection during re-challenge. These results reveal the temporal impact of XIAP in promoting the fitness of activated CD8 T cells through cell extrinsic and intrinsic mechanisms and provide a mechanistic explanation of the phenotype observed in XLP-2 patients.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011455
DOI:
10.1371/journal.ppat.1011455.g001
DOI:
10.1371/journal.ppat.1011455.g002
DOI:
10.1371/journal.ppat.1011455.g003
DOI:
10.1371/journal.ppat.1011455.g004
DOI:
10.1371/journal.ppat.1011455.g005
DOI:
10.1371/journal.ppat.1011455.g006
DOI:
10.1371/journal.ppat.1011455.g007
DOI:
10.1371/journal.ppat.1011455.s001
DOI:
10.1371/journal.ppat.1011455.s002
DOI:
10.1371/journal.ppat.1011455.s003
DOI:
10.1371/journal.ppat.1011455.s004
DOI:
10.1371/journal.ppat.1011455.s005
DOI:
10.1371/journal.ppat.1011455.s006
DOI:
10.1371/journal.ppat.1011455.s007
DOI:
10.1371/journal.ppat.1011455.s008
DOI:
10.1371/journal.ppat.1011455.s009
DOI:
10.1371/journal.ppat.1011455.r001
DOI:
10.1371/journal.ppat.1011455.r002
DOI:
10.1371/journal.ppat.1011455.r003
DOI:
10.1371/journal.ppat.1011455.r004
DOI:
10.1371/journal.ppat.1011455.r005
DOI:
10.1371/journal.ppat.1011455.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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