Staphylococcal enterotoxin B (SEB) activates TCR- and CD28-mediated inflammatory signals in the absence of MHC class II molecules

The inflammatory activity of staphylococcal enterotoxin B (SEB) relies on its capacity to trigger polyclonal T‐cell activation by binding both T‐cell receptor (TCR) and costimulatory receptor CD28 on T cells and MHC class II and B7 molecules on antigen presenting cells (APC). Previous studies highlighted that SEB may bind TCR and CD28 molecules independently of MHC class II, yet the relative contribution of these interactions to the pro‐inflammatory function of SEB remained unclear. Here, we show that binding to MHC class II is dispensable for the inflammatory activity of SEB, whereas binding to TCR, CD28 and B7 molecules is pivotal, in both human primary T cells and Jurkat T cell lines. In particular, our finding is that binding of SEB to B7 molecules suffices to trigger both TCR‐ and CD28‐mediated inflammatory signalling. We also provide evidence that, by strengthening the interaction between CD28 and B7, SEB favours the recruitment of the TCR into the immunological synapse, thus inducing lethal inflammatory signallin

CD28 individual signaling up-regulates IL-22 expression and IL-22-mediated effector functions in human T lymphocytes

IL‐22 is a member of the IL‐10 cytokine family involved in host protection against extracellular pathogens, by promoting epithelial cell regeneration and barrier functions. Dysregulation of IL‐22 production has also frequently been observed in acute respiratory distress syndrome (ARDS) and several chronic inflammatory and autoimmune diseases. We have previously described that human CD28, a crucial co‐stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signalling receptor and to induce the expression of IL‐17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL‐22. Here we characterized the role of CD28 autonomous signalling in regulating IL‐22 expression in human CD4+ T cells. We show that CD28 stimulation in the absence of TCR strongly up‐regulates IL‐22 gene expression and secretion. As recently observed for IL‐17A, we also found that CD28‐mediated regulation of IL‐22 transcription requires the cooperative activities of both IL‐6‐activated STAT3 and RelA/NF‐κ transcription factors. CD28‐mediated IL‐22 production also promotes the barrier functions of epithelial cells by inducing mucin and metalloproteases expression. Finally, by using specific inhibitory drugs, we also identified CD28‐associated class 1A phosphatidylinositol 3‐kinase (PI3K) as a pivotal mediator of CD28‐mediated IL‐22 expression and IL‐ 22‐dependent epithelial cell barrier functions

CD28 autonomous signaling orchestrates IL-22 expression and IL-22-regulated epithelial barrier functions in human T lymphocytes

IL-22 is a member of the IL-10 cytokine family involved in host protection against extracellular pathogens, by promoting epithelial cell regeneration and barrier functions. Dysregulation of IL-22 production has also frequently been observed in acute respiratory distress syndrome (ARDS) and several chronic inflammatory and autoimmune diseases. We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. Here we characterized the role of CD28 autonomous signaling in regulating IL-22 expression in human CD4+ T cells. We show that CD28 stimulation in the absence of TCR strongly up-regulates IL-22 gene expression and secretion. As recently observed for IL-17A, we also found that CD28-mediated regulation of IL-22 transcription requires the cooperative activities of both IL-6-activated STAT3 and RelA/NF-κB transcription factors. CD28-mediated IL-22 production also promotes the barrier functions of epithelial cells by inducing mucin and metalloproteases expression. Finally, by using specific inhibitory drugs, we also identified CD28-associated class 1A phosphatidylinositol 3-kinase (PI3K) as a pivotal mediator of CD28-mediated IL-22 expression and IL-22–dependent epithelial cell barrier functions

Optimality conditions in convex multiobjective SIP

The purpose of this paper is to characterize the weak efficient solutions, the efficient solutions, and the isolated efficient solutions of a given vector optimization problem with finitely many convex objective functions and infinitely many convex constraints. To do this, we introduce new and already known data qualifications (conditions involving the constraints and/or the objectives) in order to get optimality conditions which are expressed in terms of either Karusk–Kuhn–Tucker multipliers or a new gap function associated with the given problem.This research was partially cosponsored by the Ministry of Economy and Competitiveness (MINECO) of Spain, and by the European Regional Development Fund (ERDF) of the European Commission, Project MTM2014-59179-C2-1-P

Perturbed nonlocal fourth order equations of Kirchhoff type with Navier boundary conditions

Abstract We investigate the existence of multiple solutions for perturbed nonlocal fourth-order equations of Kirchhoff type under Navier boundary conditions. We give some new criteria for guaranteeing that the perturbed fourth-order equations of Kirchhoff type have at least three weak solutions by using a variational method and some critical point theorems due to Ricceri. We extend and improve some recent results. Finally, by presenting two examples, we ensure the applicability of our results

Fixed point theorems for cyclic self-maps involving weaker Meir-Keelerfunctions in complete metric spaces and applications

We obtain fixed point theorems for cyclic self-maps on complete metric spaces involving Meir-Keeler and weaker Meir-Keeler functions, respectively. In this way, we extend several well-known fixed point theorems and, in particular, improve some very recent results on weaker Meir-Keeler functions. Fixed point results for well-posed property and for limit shadowing property are also deduced. Finally, an application to the study of existence and uniqueness of solutions for a class of nonlinear integral equations is presented.The second author thanks for the support of the Ministry of Economy and Competitiveness of Spain under grant MTM2012-37894-C02-01, and the Universitat Politecnica de Valencia, grant PAID-06-12-SP20120471.Nashine, HK.; Romaguera Bonilla, S. (2013). Fixed point theorems for cyclic self-maps involving weaker Meir-Keelerfunctions in complete metric spaces and applications. Fixed Point Theory and Applications. 2013(224):1-15. https://doi.org/10.1186/1687-1812-2013-224S1152013224Kirk WA, Srinavasan PS, Veeramani P: Fixed points for mapping satisfying cyclical contractive conditions. Fixed Point Theory 2003, 4: 79–89.Banach S: Sur les operations dans les ensembles abstraits et leur application aux equations integerales. Fundam. Math. 1922, 3: 133–181.Boyd DW, Wong SW: On nonlinear contractions. Proc. Am. Math. Soc. 1969, 20: 458–464. 10.1090/S0002-9939-1969-0239559-9Caristi J: Fixed point theorems for mappings satisfying inwardness conditions. Trans. Am. Math. Soc. 1976, 215: 241–251.Di Bari C, Suzuki T, Vetro C: Best proximity points for cyclic Meir-Keeler contractions. Nonlinear Anal. 2008, 69: 3790–3794. 10.1016/j.na.2007.10.014Karapinar E: Fixed point theory for cyclic weaker ϕ -contraction. Appl. Math. Lett. 2011, 24: 822–825. 10.1016/j.aml.2010.12.016Karapinar E, Sadarangani K: Corrigendum to “Fixed point theory for cyclic weaker ϕ -contraction” [Appl. Math. Lett. Vol. 24(6), 822–825.]. Appl. Math. Lett. 2012, 25: 1582–1584. 10.1016/j.aml.2011.11.001Karapinar E, Sadarangani K:Fixed point theory for cyclic ( ϕ − φ ) -contractions. Fixed Point Theory Appl. 2011., 2011: Article ID 69Nahsine HK: Cyclic generalized ψ -weakly contractive mappings and fixed point results with applications to integral equations. Nonlinear Anal. 2012, 75: 6160–6169. 10.1016/j.na.2012.06.021Păcurar M: Fixed point theory for cyclic Berinde operators. Fixed Point Theory 2011, 12: 419–428.Păcurar M, Rus IA: Fixed point theory for cyclic φ -contractions. Nonlinear Anal. 2010, 72: 2683–2693.Piatek B: On cyclic Meir-Keeler contractions in metric spaces. Nonlinear Anal. 2011, 74: 35–40. 10.1016/j.na.2010.08.010Rus IA: Cyclic representations and fixed points. Ann. “Tiberiu Popoviciu” Sem. Funct. Equ. Approx. Convexity 2005, 3: 171–178.Chen CM: Fixed point theory for the cyclic weaker Meir-Keeler function in complete metric spaces. Fixed Point Theory Appl. 2012., 2012: Article ID 17Chen CM: Fixed point theorems for cyclic Meir-Keeler type mappings in complete metric spaces. Fixed Point Theory Appl. 2012., 2012: Article ID 41Meir A, Keeler E: A theorem on contraction mappings. J. Math. Anal. Appl. 1969, 28: 326–329. 10.1016/0022-247X(69)90031-6Matkowski J: Integrable solutions of functional equations. Diss. Math. 1975, 127: 1–68.Karapinar E, Romaguera S, Tas K: Fixed points for cyclic orbital generalized contractions on complete metric spaces. Cent. Eur. J. Math. 2013, 11: 552–560. 10.2478/s11533-012-0145-0De Blasi FS, Myjak J: Sur la porosité des contractions sans point fixed. C. R. Math. Acad. Sci. Paris 1989, 308: 51–54.Lahiri BK, Das P: Well-posedness and porosity of certain classes of operators. Demonstr. Math. 2005, 38: 170–176.Popa V: Well-posedness of fixed point problems in orbitally complete metric spaces. Stud. Cercet. ştiinţ. - Univ. Bacău, Ser. Mat. 2006, 16: 209–214. Supplement. Proceedings of ICMI 45, Bacau, Sept. 18–20 (2006)Popa VV: Well-posedness of fixed point problems in compact metric spaces. Bul. Univ. Petrol-Gaze, Ploiesti, Sec. Mat. Inform. Fiz. 2008, 60: 1–4

Interaction Pattern of Arg 62 in the A-Pocket of Differentially Disease-Associated HLA-B27 Subtypes Suggests Distinct TCR Binding Modes

The single amino acid replacement Asp116His distinguishes the two subtypes HLA-B*2705 and HLA-B*2709 which are, respectively, associated and non-associated with Ankylosing Spondylitis, an autoimmune chronic inflammatory disease. The reason for this differential association is so far poorly understood and might be related to subtype-specific HLA:peptide conformations as well as to subtype/peptide-dependent dynamical properties on the nanoscale. Here, we combine functional experiments with extensive molecular dynamics simulations to investigate the molecular dynamics and function of the conserved Arg62 of the α1-helix for both B27 subtypes in complex with the self-peptides pVIPR (RRKWRRWHL) and TIS (RRLPIFSRL), and the viral peptides pLMP2 (RRRWRRLTV) and NPflu (SRYWAIRTR). Simulations of HLA:peptide systems suggest that peptide-stabilizing interactions of the Arg62 residue observed in crystal structures are metastable for both B27 subtypes under physiological conditions, rendering this arginine solvent-exposed and, probably, a key residue for TCR interaction more than peptide-binding. This view is supported by functional experiments with conservative (R62K) and non-conservative (R62A) B*2705 and B*2709 mutants that showed an overall reduction in their capability to present peptides to CD8+ T cells. Moreover, major subtype-dependent differences in the peptide recognition suggest distinct TCR binding modes for the B*2705 versus the B*2709 subtype