Dataset Information

C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism.

ABSTRACT: Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of systemic lupus erythematosus (SLE). Explaining this association in terms of abnormalities in the classical pathway alone remains problematic because C3 deficiency does not predispose to SLE. Here, using a mouse model of SLE, we demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8+ T cells, which can themselves propagate autoimmunity. C1q deficiency also triggers an exuberant effector CD8+ T cell response to chronic viral infection leading to lethal immunopathology. These data establish a link between C1q and CD8+ T cell metabolism and may explain how C1q protects against lupus, with implications for the role of viral infections in the perpetuation of autoimmunity.

SUBMITTER: Ling GS

PROVIDER: S-EPMC6545171 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

C1q restrains autoimmunity and viral infection by regulating CD8<sup>+</sup> T cell metabolism.

Ling Guang Sheng GS Crawford Greg G Buang Norzawani N Bartok Istvan I Tian Kunyuan K Thielens Nicole M NM Bally Isabelle I Harker James A JA Ashton-Rickardt Philip G PG Rutschmann Sophie S Strid Jessica J Botto Marina M

Science (New York, N.Y.) 20180501 6388

Deficiency of C1q, the initiator of the complement classical pathway, is associated with the development of systemic lupus erythematosus (SLE). Explaining this association in terms of abnormalities in the classical pathway alone remains problematic because C3 deficiency does not predispose to SLE. Here, using a mouse model of SLE, we demonstrate that C1q, but not C3, restrains the response to self-antigens by modulating the mitochondrial metabolism of CD8<sup>+</sup> T cells, which can themselve ...[more]

PMID: 29724957

Similar Datasets

Project description:Acute and chronic viral infections result in the differentiation of effector and exhausted T cells with functional and phenotypic differences that dictate whether the infection is cleared or progresses to chronicity. High CD38 expression has been observed on CD8+ T cells across various viral infections and tumors in patients, suggesting an important regulatory function for CD38 on responding T cells. Here, we show that CD38 expression was increased and sustained on exhausted CD8+ T cells following chronic lymphocytic choriomeningitis virus (LCMV) infection, with lower levels observed on T cells from acute LCMV infection. We uncovered a cell-intrinsic role for CD38 expression in regulating the survival of effector and exhausted CD8+ T cells. We observed increased proliferation and function of Cd38-/- CD8+ progenitor exhausted T cells compared to those of wild-type (WT) cells. Furthermore, decreased oxidative phosphorylation and glycolytic potential were observed in Cd38-/- CD8+ T cells during chronic but not acute LCMV infection. Our studies reveal that CD38 has a dual cell-intrinsic function in CD8+ T cells, where it decreases proliferation and function yet supports their survival and metabolism. These findings show that CD38 is not only a marker of T cell activation but also has regulatory functions on effector and exhausted CD8+ T cells. IMPORTANCE Our study shows how CD38 expression is regulated on CD8+ T cells responding during acute and chronic viral infection. We observed higher CD38 levels on CD8+ T cells during chronic viral infection compared to levels during acute viral infection. Deleting CD38 had an important cell-intrinsic function in ensuring the survival of virus-specific CD8+ T cells throughout the course of viral infection. We found defective metabolism in Cd38-/- CD8+ T cells arising during chronic infection and changes in their progenitor T cell phenotype. Our studies revealed a dual cell-intrinsic role for CD38 in limiting proliferation and granzyme B production in virus-specific exhausted T cells while also promoting their survival. These data highlight new avenues for research into the mechanisms through which CD38 regulates the survival and metabolism of CD8+ T cell responses to viral infections.

Dataset Information

C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism.

Publications

C1q restrains autoimmunity and viral infection by regulating CD8<sup>+</sup> T cell metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

C1q restrains autoimmunity and viral infection by regulating CD8+ T cell metabolism.

Publications

C1q restrains autoimmunity and viral infection by regulating CD8&lt;sup&gt;+&lt;/sup&gt; T cell metabolism.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

C1q restrains autoimmunity and viral infection by regulating CD8<sup>+</sup> T cell metabolism.