Defective CD8+CD28− regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy

Ceeraz, Sabrina; Hall, Christopher; Choy, Ernest; Spencer, Jo; Corrigall, Valerie

doi:10.1111/cei.12161

Cited by 35 publications

(27 citation statements)

References 27 publications

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“…Thus, by inducing GrB 1 CD8 1 T cells, 4BL cells inhibit the growth of poorly immunogenic B16 melanoma cells in old mice, suggesting that, at least in part, 4BL cells may also be responsible for a paradoxical aging-associated reduced growth of some tumors in mice and humans. [27][28][29] Alternatively, these results raise an interesting possibility that 4BL cells may also participate in accumulation of CD8 1 CD28 -T cells in RA, MS, and T1D 17,19,46 that respond to low-threshold stimuli and secrete perforin and GrB. 12,13 As in Old-depleted and Old-restored mice, which lost activated CD8 1 T cells and could not retard tumor growth after 4BL depletion, depletion of B cells also impairs antigen-specific T-cell activation 25 and ameliorates RA, MS, and T1D.…”

Section: Discussionmentioning

confidence: 90%

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

Lee-Chang¹,

Bodogai²,

Moritoh³

et al. 2014

Blood

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Although the accumulation of highly-differentiated and granzyme B (GrB)-expressing CD8(+)CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques, and mice, and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+)CD8(+) T cells by presenting endogenous antigens and using the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and its capacity to evoke the generation of GrB(+)CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4-1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly.

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Section: Discussionmentioning

confidence: 90%

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

Lee-Chang¹,

Bodogai²,

Moritoh³

et al. 2014

Blood

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“…These two inhibitory molecular display long cytoplasmic tails containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and inhibit cell activation by recruiting protein tyrosine phosphatase SHP-1, thus they can render tolerogenic APC and block their co-stimulated capacity (Ravetch & Lanier, 2000). The tolerized APC, in turn, can anergize effector T cells, further inhibiting the activation and amplification of T cells (Cortesini et al, 2001), (ii) Ts cells can inhibit T cell activation by secreting the suppressive cytokine IL10 (Ceeraz et al, 2013). Regarding the vital roles of the control of self-reactive T cells and sustaining immune tolerance, Ts cell abnormalities are related to cancer immune escape, graft rejection and autoimmunity (Lin et al, 2009;Mikulkova et al, 2010;Scarsi et al, 2011;Chen et al, 2014;Li et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Although CD8 + Ts cells play a vital role in immune tolerance (Najafian et al, 2003;Filaci et al, 2007), there are conflicting results regarding their abnormality in autoimmune diseases (Tulunay et al, 2008;Mikulkova et al, 2010;Slowik et al, 2012;Ceeraz et al, 2013;Dai et al, 2013;Yarde et al, 2014). What is the reason for this contradiction?…”

Section: Discussionmentioning

confidence: 99%

Numerical and functional defects in CD8⁺CD28⁻ T‐suppressor lymphocytes from patients with primary immune thrombocytopenia

Hao

Zhang

et al. 2017

Br J Haematol

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Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, and loss of immune tolerance has been implicated in ITP pathogenesis. CD8 CD28 suppressor (Ts) cells have an immunosuppression function and are involved in several autoimmune disorders. However, the role of Ts cells in ITP is currently not clear. Here, flow cytometry was used to detect the CD8 CD28 CD127 proportion, which was decreased in active ITP patients compared with that of controls. Function analysis showed that immunosuppression of CD8 CD28 Ts cells in ITP patients was impaired. Mechanistic studies have shown that CD8 CD28 Ts cells from controls can downregulate CD80 and upregulate LILRB4 (ITL3) and LILRB2 (ILT4) expression on CD14 monocytes, whereas these abilities were not found in Ts cells from ITP patients. Furthermore, Inducible T-cell costimulatory (ICOS) expression on the Ts cell surface after activation was decreased whereas programmed death 1 and interleukin 10 expression was not changed in ITP patients compared with those of controls. In summary, the down-regulated quantity and function of Ts cells in active patients indicated that a Ts defect was involved in ITP. Moreover, decreased ICOS expression and the loss of the ability to regulate co-stimulator expression on antigen-presenting cells partly explained the defective Ts-mediated suppression.

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“…In vitro studies using human peripheral blood mononuclear cells found that RPM caused an increase in the numbers of CD103+CD8+ alloreactive T cells with immunosuppressive properties, while CsA had no significant effect on the percentage of these cells and prednisolone diminished the numbers of these cells (98). CD8+CD28- Treg function was improved in rheumatoid arthritis patients that received TNF-α inhibitor therapy, while patients treated with methotrexate had no effects on the defective CD8+CD28- Treg activity normally found in these patients (99). There is a dearth of published reports on the effects of immunosuppressive agents on Tr1 Tregs and DN T regs activity in the context of allograft and xenograft survival.…”

Section: Effect Of Immunosuppressive Agents On Treg Generation and Fumentioning

confidence: 99%

Advances on Non-CD4 + Foxp3+ T Regulatory Cells

Ligocki

Niederkorn

2015

Transplantation

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The overwhelming body of research on T regulatory cells (Tregs) has focused on CD4+CD25+Foxp3+ T cells. However, recent years have witnessed a resurgence in interest in CD4-CD8+, CD4-CD8- (double negative; DN), and CD4+Foxp3- Tr1 Tregs and their role in controlling autoimmune diseases and in promoting the survival of organ allografts and xenografts. CD8+ and DN Tregs can arise spontaneously (natural Tregs) or can be induced in situ. Both CD8+ and DN Tregs have been shown to enhance the survival of organ allografts and xenografts. Additionally, both can suppress alloimmune responses by contact-dependent mechanisms by either inducing apoptosis or mediating direct cytolysis of effector T cells. CD8+, DN, and Tr1 Tregs can also act in a contact-independent manner by elaborating soluble immunosuppressive factors such TGF-β and IL-10. Applying CD8+, DN, and Tr1 Tregs for enhancing the survival of organ allografts and xenografts is still in its infancy but holds significant potential. Furthermore, there is a need for a more comprehensive understanding of how current immunosuppressive therapies applied to organ transplantations affect the wide array of Treg populations.

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Defective CD8+CD28− regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy

Cited by 35 publications

References 27 publications

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

Numerical and functional defects in CD8⁺CD28⁻ T‐suppressor lymphocytes from patients with primary immune thrombocytopenia

Advances on Non-CD4 + Foxp3+ T Regulatory Cells

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Defective CD8+CD28− regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy

Cited by 35 publications

References 27 publications

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity

Numerical and functional defects in CD8+CD28− T‐suppressor lymphocytes from patients with primary immune thrombocytopenia

Advances on Non-CD4 + Foxp3+ T Regulatory Cells

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Product

Resources

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Numerical and functional defects in CD8⁺CD28⁻ T‐suppressor lymphocytes from patients with primary immune thrombocytopenia