Nonapoptotic and Extracellular Activity of Granzyme B Mediates Resistance to Regulatory T Cell (Treg) Suppression by HLA-DR(-)CD25(hi) CD127(lo) Tregs in Multiple Sclerosis and in Response to IL-6
JOURNAL OF IMMUNOLOGY
2015; 194 (5): 2180-2189
In autoimmune patients, regulatory T cells (Tregs) are increasingly found to be unable to suppress patient-derived T cells, an outcome referred to as Treg resistance. In this study, we show that CD4 T cells from patients with multiple sclerosis resist suppression by patient-derived or healthy donor-derived ex vivo Tregs. Importantly, we report that granzyme B (GzmB) contributes to this Treg resistance via a novel, apoptosis-independent mechanism. We show that memory CD4(+)CD127(lo)FOXP3(+) Treg subsets do not express GzmB, whereas activated, nonregulatory CD4 T cells isolated from patients with multiple sclerosis express higher levels of GzmB than do cells from healthy donors. In contrast to the intracellular GzmB that mediates apoptosis, GzmB can be found in extracellular fluids where it is hypothesized to regulate other cellular processes. In this study, we show that providing extracellular GzmB strongly inhibits Treg suppression, without altering Treg viability. However, when GzmB and GzmB-specific inhibitor are both provided to the cocultures, Treg suppression occurs. Thus, these data suggest that a novel activity of extracellular GzmB is to regulate Treg suppression. Additionally, we find that the suppression-abrogating cytokine IL-6 augments GzmB expression by human CD4 T cells, and it inhibits Treg suppression via this nonapoptotic GzmB-mediated mechanism. Lastly, in examining the mechanism whereby GzmB inhibits Treg function, we show that extracellular GzmB reduces Treg expression of CD39 and programmed death ligand 1. Collectively, these data indicate that extracellular GzmB plays an unexpected, nonapoptotic role in regulating Treg suppression and suggest that inactivation of specifically the extracellular activity of GzmB may be an efficacious therapeutic in autoimmunity.
View details for DOI 10.4049/jimmunol.1303257
View details for Web of Science ID 000350023900019
View details for PubMedID 25637022
- The future of biologics: Applications for food allergy JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2015; 135 (2): 312-323
The future of biologics: applications for food allergy.
journal of allergy and clinical immunology
2015; 135 (2): 312-323
Allergic diseases affect millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy; however, some subjects experience treatment-resistant inflammation or adverse reactions to these treatments, and there are currently no approved therapeutics for the treatment of food allergy. There is a dire need for new therapeutic approaches for patients with poorly controlled atopic diseases and a need to improve the safety and effectiveness of allergen immunotherapy. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small-molecule inhibitors of cell signaling, anti-type 2 cytokine mAbs, and TH1-promoting adjuvants.
View details for DOI 10.1016/j.jaci.2014.12.1908
View details for PubMedID 25662303
The Potential of Anti-IgE in Food Allergy Therapy.
Current treatment options in allergy
2014; 1 (2): 145-156
View details for PubMedID 25419508
- ATP release and autocrine signaling through P2X4 receptors regulate ?? T cell activation. Journal of Leukocyte Biology 2012; 92 (4): 787-794
Hypertonic stress regulates T cell function via pannexin-1 hemichannels and P2X receptors
JOURNAL OF LEUKOCYTE BIOLOGY
2010; 88 (6): 1181-1189
Hypertonic saline (HS) resuscitation increases T cell function and inhibits posttraumatic T cell anergy, which can reduce immunosuppression and sepsis in trauma patients. We have previously shown that HS induces the release of cellular ATP and enhances T cell function. However, the mechanism by which HS induces ATP release and the subsequent regulation of T cell function by ATP remain poorly understood. In the present study, we show that inhibition of the gap junction hemichannel pannexin-1 (Panx1) blocks ATP release in response to HS, and HS exposure triggers significant changes in the expression of all P2X-type ATP receptors in Jurkat T cells. Blocking or silencing of Panx1 or of P2X1, P2X4, or P2X7 receptors blunts HS-induced p38 MAPK activation and the stimulatory effects of HS on TCR/CD28-induced IL-2 gene transcription. Moreover, treatment with HS or agonists of P2X receptors overcomes T cell suppression induced by the anti-inflammatory cytokine IL-10. These findings indicate that Panx1 hemichannels facilitate ATP release in response to hypertonic stress and that P2X1, P2X4, and P2X7 receptor activation enhances T cell function. We conclude that HS and P2 receptor agonists promote T cell function and thus, could be used to improve T cell function in trauma patients.
View details for DOI 10.1189/jlb.0410211
View details for Web of Science ID 000285867500016
View details for PubMedID 20884646