Therapeutic potential of CD8+ cytotoxic T lymphocytes in SLE

Puliaeva, Irina; Puliaev, Roman; Via, Charles S.

doi:10.1016/j.autrev.2008.07.045

Cited by 37 publications

(32 citation statements)

References 39 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another possibility is that TNF-related apoptosis inducing ligand (TRAIL) produced by CTLs in the presence of IL-2 may induce DN T cell apoptosis. Given that CD8 + T cell function is impaired in both human and lupus-prone mice (51), IL-2 may restore CTL function that contributes to the elimination of pathogenic lymphocytes including DN T cells in MRL/ lpr mice. Taken together, our results suggest that CTLs treated with IL-2 can affect the pathogenic DN T cell viability and expansion.…”

Section: Discussionmentioning

confidence: 99%

IL-2 Protects Lupus-Prone Mice from Multiple End-Organ Damage by Limiting CD4−CD8− IL-17–Producing T Cells

Mizui

Koga

Lieberman

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Interleukin-2 (IL-2), a cytokine with pleiotropic effects, is critical for immune cell activation and peripheral tolerance. Although the therapeutic potential of IL-2 has been previously suggested in autoimmune diseases, the mechanisms whereby IL-2 mitigates autoimmunity and prevents organ damage remains unclear. Using an inducible recombinant adeno-associated virus (rAAV) vector we investigated the effect of low systemic levels of IL-2 in lupus-prone MRL/Faslpr/lpr (MRL/lpr) mice. Treatment of mice after the onset of disease with IL-2-rAAV resulted in reduced mononuclear cell infiltration and pathology of various tissues including skin, lungs and kidneys. In parallel, we noted a significant decrease of IL-17-producing CD3+CD4−CD8− double-negative T cells and an increase in CD4+CD25+Foxp3+ immunoregulatory T cells (Treg) in the periphery. We also show that IL-2 can drive DN T cell death through an indirect mechanism. Notably, targeted delivery of IL-2 to CD122+ cytotoxic lymphocytes effectively reduced the number of DN T cells and lymphadenopathy whereas selective expansion of Treg by IL-2 had no effect on DN T cells. Collectively, our data suggest that administration of IL-2 to lupus-prone mice protects against end-organ damage and suppresses inflammation by dually limiting IL-17-producing DN T cells and expanding Treg.

show abstract

Section: Discussionmentioning

confidence: 99%

IL-2 Protects Lupus-Prone Mice from Multiple End-Organ Damage by Limiting CD4−CD8− IL-17–Producing T Cells

Mizui

Koga

Lieberman

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…4A, columns 1 & 3 respectively) consistent with a failure of DBA CD8 CTL maturation. These positive controls for acute and chronic GVHD phenotype demonstrate that: a) purification and recombination of CD4 and CD8 T cell subsets does not alter the expected two week phenotypes observed in unfractionated donor splenocyte transfer experiments (35), and b) T cells are necessary and sufficient for GVHD induction.…”

Section: Resultsmentioning

confidence: 88%

“…Comparing day 14 host B cell numbers, control matched B10.D2 CD4 + B10.D2 CD8 (matched B10.D2→F1) donor cells induce significant and profound host B cell elimination compared to uninjected F1 mice (Fig. 4A, columns 1 & 2 from the left) typical of an acute GVHD cytotoxic phenotype and indicative of a strong B10.D2 CD8 CTL response (35). In contrast, matched DBA CD4 and DBA CD8 donor T cells (matched DBA→F1) induce significant host B cell expansion typical of the expected day 14 stimulatory chronic GVHD (Fig.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic Differences in Donor CD4 T Cell IL-2 Production Influence Severity of Parent-into-F1 Murine Lupus by Skewing the Immune Response Either toward Help for B Cells and a Sustained Autoantibody Response or toward Help for CD8 T Cells and a Downregulatory Th1 Response

Soloviova

Puliaiev

Haas

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Using the parent-into-F1 model of induced lupus and (C57Bl/6xDBA2) F1 mice as hosts, we compared the inherent lupus-inducing properties of the two parental strain CD4 T cells. To control for donor CD4 recognition of alloantigen, we used H-2d identical DBA/2 and B10.D2 donor T cells. We demonstrate that these two normal, non-lupus prone parental strains exhibit two different T cell activation pathways in vivo. B10.D2 CD4 T cells induce a strong Th1/CMI pathway characterized by IL-2/IFN-g expression, help for CD8 CTL, skewing of DC subsets towards CD8a DC, coupled with reduced CD4Tfh cells and transient B cell help. By contrast, DBA/2 CD4 T cells exhibit a reciprocal, lupus-inducing pathway characterized by poor IL-2/IFN-g expression, poor help for CD8 CTL, skewing of DC subsets towards pDC coupled with greater CD4 Tfh cells, prolonged B cell activation, autoantibody formation, and lupus-like renal disease. Additionally, two distinct in vivo splenic gene expression signatures were induced. In vitro analysis of TCR signaling revealed defective DBA CD4 T cell induction of NF-κB, reduced degradation of IκBα and increased expression of the NF-κB regulator A20. Thus, attenuated NF-κB signaling may lead to diminished IL-2 production by DBA CD4 T cells. These results indicate that intrinsic differences in donor CD4 IL-2 production and subsequent immune skewing could contribute to lupus susceptibility in humans. Therapeutic efforts to skew immune function away from excessive help for B cells and towards help for CTL may be beneficial.

show abstract

“…B cells are activated, expanded, and initially produce anti-ssDNA ab. Because host splenocytes are significantly reduced in acute GVHD and increased in chronic GVHD at 2 weeks, the 2-week phenotypes have been designated as cytotoxic and stimulatory, respectively [33]. …”

Section: Insights Into Lupus-associated Ctl and Il-2 Defects From Thementioning

confidence: 99%

Defectivein vitroIL-2 production in lupus is an early but secondary event paralleling disease activity: Evidence from the murine parent-into-F1 model supports staging of IL-2 defects in human lupus

Via

Shearer

2009

Autoimmunity

View full text Add to dashboard Cite

T cell defects are a well described feature of both human and murine lupus however their exact significance is unclear. Evidence from an induced model of lupus, the P → F1 model of chronic lupus-like GVHD demonstrates that a secondary inducible T cell defect in in vitro IL-2 and CTL responses occurs early in the course of lupus-like disease and well in advance of clinical disease. Defective Th cell function was probed using a novel approach categorizing the response to two stimuli:1) the MHC self restricted response, termed self + X; and 2) the allogeneic response. Using this approach, lupus mice exhibited similar in vitro Th cell pattern i.e. and absent S + X response but preserved allogeneic (termed −/+). In contrast, human lupus patients exhibited three possible response patters, +/+, −/+ or −/− with more severe in vitro T cell impairment correlated with more severe disease. Similarly, patients with other T cell mediated conditions i.e. HIV infection or renal allograft recipients, also exhibited more severe in vitro T cell impairment with greater disease activity or greater immunosuppression respectively. The similar Th response patterns in human and murine T cell mediated conditions indicates that the underlying mechanisms involved are not disease specific but instead reflect common immune responses and validate the use of the P → F1 model for future studies of T cell mediated conditions. These results support the use of prospective monitoring of IL-2 responses in lupus patients. Successful adaptation of this approach to the clinical setting could allow not only earlier therapeutic intervention and reduced organ damage but also earlier tapering of pharmacological agents and reduced untoward effects.

show abstract

Therapeutic potential of CD8+ cytotoxic T lymphocytes in SLE

Cited by 37 publications

References 39 publications

IL-2 Protects Lupus-Prone Mice from Multiple End-Organ Damage by Limiting CD4−CD8− IL-17–Producing T Cells

IL-2 Protects Lupus-Prone Mice from Multiple End-Organ Damage by Limiting CD4−CD8− IL-17–Producing T Cells

Intrinsic Differences in Donor CD4 T Cell IL-2 Production Influence Severity of Parent-into-F1 Murine Lupus by Skewing the Immune Response Either toward Help for B Cells and a Sustained Autoantibody Response or toward Help for CD8 T Cells and a Downregulatory Th1 Response

Defectivein vitroIL-2 production in lupus is an early but secondary event paralleling disease activity: Evidence from the murine parent-into-F1 model supports staging of IL-2 defects in human lupus

Contact Info

Product

Resources

About