Pro‐inflammatory self‐reactive T cells are found within murine TCR‐αβ+CD4−CD8−PD‐1+ cells

Rodríguez-Rodríguez, Noé; Apostolidis, Sokratis A.; Fitzgerald, Lauren; Meehan, Bronwyn S.; Corbett, Alexandra J.; Martín-Villa, José Manuel; McCluskey, James; Tsokos, George C.; Crispín, José C.

doi:10.1002/eji.201546056

Cited by 39 publications

(27 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, IL-23 is essential for lymphadenopathy and DN T cell expansion, as disrupted signaling by this cytokine leads to lower numbers of DN T cells (22). The active state of DN cells is supported by recent findings that normal programmed cell death protein 1-expressing DN cells are pro-inflammatory and respond to self-antigens (25, 26) and by their association with human lupus (27, 28). …”

Section: Hyperproliferation Of All Lpr Mouse T Cell Subsetsmentioning

confidence: 86%

On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

et al. 2017

View full text Add to dashboard Cite

Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.

show abstract

Section: Hyperproliferation Of All Lpr Mouse T Cell Subsetsmentioning

confidence: 86%

On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

et al. 2017

View full text Add to dashboard Cite

show abstract

“…This suggests preexisting DN T cells either had increased survival or increased proliferation compared to CD4 and CD8 T cells, or that coreceptor expressing cells had downregulated their coreceptor. While in some cases DN T cells can have proinflammatory activity and may even be effectors in disease [32,66,67], DN T cells have frequently been associated with suppression of responses, both in mice and in humans [32,33,68]. For example, DN T cells are associated with suppression of graft versus host disease [69,70], and they reduce diabetes in association with a reduction in autoantibodies [34,71].…”

Section: Discussionmentioning

confidence: 99%

Anti‐CD52 blocks EAE independent of PD‐1 signals and promotes repopulation dominated by double‐negative T cells and newly generated T and B cells

et al. 2020

View full text Add to dashboard Cite

Lymphocyte depletion using anti‐CD52 antibody effectively reduces relapses of multiple sclerosis (MS). To begin to understand what mechanisms might control this outcome, we examined the effect of a murine‐CD52‐specific mAb on the depletion and repopulation of immune cells in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. We tested whether the tolerance‐promoting receptor programmed cell death protein‐1 (PD‐1) is required for disease remission post anti‐CD52, and found that PD‐1‐deficient mice with a more severe EAE were nevertheless effectively treated with anti‐CD52. Anti‐CD52 increased the proportions of newly generated T cells and double‐negative (DN) T cells while reducing newly generated B cells; the latter effect being associated with a higher expression of CD52 by these cells. In the longer term, anti‐CD52 caused substantial increases in the proportion of newly generated lymphocytes and DN T cells in mice with EAE. Thus, the rapid repopulation of lymphocytes from central lymphoid organs post anti‐CD52 may limit further disease. Furthermore, these data identify DN T cells, a subset with immunoregulatory potential, as a significant hyperrepopulating subset following CD52‐mediated depletion.

show abstract

“…Double-Negative (DN) T cells, defined as TCRαβ + CD4 − CD8 − , can result from inactivation or exhaustion of autoreactive, or continuously stimulated CD8 T cells, such as are found in chronic infection [12,13]. Under normal conditions an immunosuppressive role has been attributed to these cells, both in mouse and human, through antigen-competition and T cell killing by Fas-FasL or perforin and granzyme secretion [14,15].…”

Section: Double-negative T Cells In Sle: From Suppressive To Pro-inflmentioning

confidence: 99%

T cells in Systemic Lupus Erythematosus

Suárez‐Fueyo

Bradley

Tsokos

2016

Current Opinion in Immunology

179

127

View full text Add to dashboard Cite

Systemic Lupus Erythematosus is an autoimmune disorder caused by a complex combination of genetic, epigenetic and environmental factors. Different polymorphisms and epigenetic modifications lead to altered gene expression and function of several molecules which lead to abnormal T cell responses. Metabolic and functional alterations result in peripheral tolerance failures and biased differentiation of T cells into pro-inflammatory and B cell-helper phenotypes as well as the accumulation of disease-promoting memory T cells. Understanding these T cell alterations and their origins is necessary to develop more accurate patient classification systems and to discover new therapeutic targets.

show abstract

Pro‐inflammatory self‐reactive T cells are found within murine TCR‐αβ⁺CD4⁻CD8⁻PD‐1⁺ cells

Cited by 39 publications

References 49 publications

On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

Anti‐CD52 blocks EAE independent of PD‐1 signals and promotes repopulation dominated by double‐negative T cells and newly generated T and B cells

T cells in Systemic Lupus Erythematosus

Contact Info

Product

Resources

About