CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation

Abstract

IL-17-producing CD4 IntroductionIL-17 producing CD4 ϩ T helper (Th17) cells are important in immunity against extracellular pathogens, in particular at the mucosa, and are implicated in a variety of immune-mediated inflammatory disorders. Similar to other effector T cell types, Th17 cells develop from naive CD4 ϩ T cells in response to antigen presenting cell (APC)-derived signals. Whereas the cytokines IL-1␤, IL-6, IL-23, and TGF-␤ have been identified to support Th17 differentiation in both mice and human, there is less consensus on the costimulatory signals that drive the development of human Th17 cells. [1][2][3][4] A basic principle of T-cell activation is that proper stimulation of naive T cells requires costimulation via CD28 for survival and expansion, which licenses their subsequent development into distinct effector Th subsets driven by appropriate signal 3 factors. Surprisingly, 2 recent studies reported that Th17 development is selectively inhibited by CD28 costimulation. 5,6 One of these studies suggested that human Th17 development is alternatively mediated via ligation of the inducible costimulator (ICOS). 6 Among the other molecules that may alternatively costimulate CD4 ϩ T cells are the lymphocyte receptor CD5 and CD6. 7,8 CD5 and CD6 are both group B members of the Scavenger Receptor Cystein-Rich domains superfamily (SRCR-SF). CD5 and CD6 share important structural and functional properties, and have probably arisen from a common ancestral gene. During interaction between the APC and T cell, CD5 and CD6 form part of the immunologic synapse. 9,10 This localization makes them well positioned to modulate the signals that follow antigen-specific T-cell receptor (TCR) ligation. For CD5, this concept has been most clearly demonstrated. CD5 plays a role in the late events of synapse-mediated signal transduction, whereby the large cytoplasmatic domain of CD5 can recruit both positive and negative regulators of T-cell signaling. Consequently, CD5 is a modulator of T-cell responses with both stimulatory and inhibitory activities. 8,11 In the thymus, CD5 plays a role in regulating TCR-mediated expansion and survival during T-cell ontogeny. 7,8,12 In peripheral resting CD4 ϩ T cells, CD5 costimulation results in proliferation levels as high as obtained with classic CD28-mediated costimulation. A possible role of CD5-mediated costimulation of T cells in Th17 cell development is favored by the finding that mice deficient in signaling between CD5 and CK-2, a prosurvival serine/threonine kinase that associates with CD5, show diminished populations of IL-17-expressing T cells in the central nervous system, in a model of experimental autoimmune encephalomyelitis. 13 In the present study, we show that costimulation via CD5 or CD6 is superior to classic CD28 costimulation in driving Th17 cell development from human naive CD4 ϩ T cells. CD5 induces high and consistent levels of IL-17, indicating the induction of stable terminal differentiation. Indeed, CD5 promotes elevated expression of various intracellular fact...

CD55 Costimulation Induces Differentiation of a Discrete T Regulatory Type 1 Cell Population with a Stable Phenotype

“…On subsequent stimulation, the Tr1 cells maintain their phenotype over multiple rounds of CD55 costimulation. These data identify that CD55 is as potent a costimulatory molecule for naive CD4 + cells as CD28, 4-1BB, ICAM-1, and CD5 (25,29,37).…”

“…This is classically achieved with CD28 engagement by CD80/86 on DCs (24), which results in activation, differentiation, and licensing of a T helper effector phenotype (23,25), with the phenotype being heavily influenced by a third signal, the cytokine milieu (26,27). Although CD28 is a potent inducer of CD4 + cell differentiation, costimulation through other surface receptors (25,28), including 4-1BB, ICAM-1, CD2, CD44, CD9, and CD5, has been shown to act as alternative pathways for Th1, Th2, and Th17 differentiation (25,28,29).…”

A type of human skin dendritic cell marked by CD5 is associated with the development of inflammatory skin disease

“…Although there is no confirmed ligand for CD5, a recent study suggests that CD5 may be homophilic, binding CD5 on the surface of other cells (36). In addition, it was also shown that the ligation of CD5 on T cells results in the polarization of naive T cells into the Th17 pathway (37), and, more recently, in the mouse, a CD5-like molecule (CD5L) was shown to regulate the pathogenicity of Th17 (38,39). Thus, we surmised that CD5 on DCs might bind to CD5 (or CD5L) on T cells, resulting in effector T cell polarization.…”

Response: priming of human naive CD4+ T cells via CD5 costimulation requires IL-6 for optimal Th17 development

“…Still, relapse remains an open issue: in the haploidentical setting, we and others demonstrated that more than one-third of posttransplantation relapses are due to the de novo genomic loss of patient-specific HLA in leukemic blasts, which favors immune evasion from donor T cells. 1,2 Although highly relevant in the haploidentical context, HLA loss has been poorly assessed after matched unrelated donor (MUD) HSCT, 3 which is 10 times more frequent in clinical practice. 4 Here we report on a 36-year-old woman with normal karyotype AML, positive for the FLT3 internal tandem duplication (ITD) at diagnosis (clinical course in Figure 1A).…”

“…The genomic alteration spanned approximately 40 Mb and resulted in the loss of the HLA haplotype encompassing the C*02:02 and DPB1*04:02 mismatched alleles ( Figure 1B and C), with the same mechanism described for relapses after haploidentical HSCT. 1,2 This observation suggests that a primeval leukemic clone, even though negative for FLT3-ITD (mapped to chromosome 13), may have persisted during the course of treatments and reappeared upon the immune advantage granted by genomic HLA…”