The molecular signature of murine T cell homeostatic proliferation reveals both inflammatory and immune inhibition patterns

Abstract

T lymphocyte homeostatic proliferation, driven by the engagement of T cell antigen receptor with self-peptide/major histocompatibility complexes, and signaling through the common γ-chain-containing cytokine receptors, is critical for the maintenance of the T cell compartment and is regulated by the Fas death receptor (Fas, CD95). In the absence of Fas, Fas-deficient lymphoproliferation spontaneous mutation (Ipr) mice accumulate homeostatically expanded T cells. The functional consequences of sequential rounds of homeostatic expansion are not well defined. We thus examined the gene expression profiles of murine wild-type and Fas-deficient Ipr CD8+ T cell subsets that have undergone different amounts of homeostatic proliferation as defined by their level of CD44 expression, and the CD4−CD8−TCRαβ+ T cell subset that results from extensive homeostatic expansion of CD8+ T cells. Our studies show that recurrent T cell homeostatic proliferation results in global gene expression changes, including the progressive upregulation of both cytolytic proteins such as Fas-Ligand and granzyme B as well as inhibitory proteins such as programmed cell death protein 1 (PD-1) and lymphocyte activating 3 (Lag3). These findings provide an explanation for how augmented T cell homeostatic expansion could lead to the frequently observed clinical paradox of simultaneous autoinflammatory and immunodeficiency syndromes and provide further insight into the regulatory programs that control chronically stimulated T cells.

Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lprmice

“…The increased aerobic glycolysis of CD4 -CD8 -TCR-αβ + T cells is consistent with the known rapid proliferation by this subset in vivo. 22 This is paralleled by increased spontaneous cell death of the CD4 -CD8 -TCR-αβ + T cells compared with the CD4 + and CD8 + T cell subsets (figure 1D), consistent with previous observations that high levels of glycolysis in T cells, including CD4 -CD8 -TCR-αβ + T cells, drives high levels of active caspase-3, rendering them prone to cell death. 23 24 Such increased cell death could contribute to the inflammatory response in these mice.…”

“…42 Gene expression profiling of these wild-type derived CD4 -CD8 -TCR-αβ + T cells has revealed upregulation of genes for programmed cell death 1 (PD-1), interleukin 17, IFNγ, C-X-C Motif Chemokine Ligand 2 (CXCL2) and downregulation of CD127, 43 exactly the same pattern observed in lpr CD4 -CD8 -TCR-αβ + T cells. 22 Thus, these unusual T cells are not unique to Fas-deficient lpr mice. These findings, in addition to our previous observations that T-cell homeostatic proliferation also leads to the upregulation of genes involved with cytolysis and inflammation 22 on September 30, 2020 by guest.…”

“…22 Thus, these unusual T cells are not unique to Fas-deficient lpr mice. These findings, in addition to our previous observations that T-cell homeostatic proliferation also leads to the upregulation of genes involved with cytolysis and inflammation 22 on September 30, 2020 by guest. Protected by copyright.…”

“…These might include the development of lymphadenopathy of MRL-lpr mice, the generation of CD4 -CD8 -TCR-αβ + T cells and the production of autoantibodies, which may result from the absence of cell death occurring during homeostatic proliferation of lymphocytes. 17 48 Consequently, the upregulation of genes during T-cell homeostatic proliferation involved with cytolysis and inflammation, such as granzyme B, perforin and Fasligand, 22 is likely to still contribute to inflammation during MitoQ therapy. Thus, fully effective therapy for SLE may require a combination of traditional immunosuppression with non-immune antioxidant therapy.…”

Allergen Exposure in Lymphopenic Fas-Deficient Mice Results in Persistent Eosinophilia Due to Defects in Resolution of Inflammation

“…However, we have yet to determine whether polyclonal stimuli could replace homeostatic proliferation and play a role in the prolonged eosinophilia found in our model. Recently, it has been shown that recurrent T cell homeostatic proliferation results in global gene expression changes, including the progressive upregulation of FasL, granzyme B, and programmed cell death protein 1 (PD-1) ( 39 ). Considering that PD-1 is expressed during chronic T cell activation and recurrent T cell homeostatic proliferation, and considering that PD-1 expression on T cells inhibits IFN-γ production ( 40 ), it is possible that PD-1 may play a role on our model.…”