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

Abstract

Unlike other helper T cells, the costimulatory ligands responsible for T regulatory type 1 (Tr1) cell differentiation remain undefined. Understanding the molecular interactions driving peripheral Tr1 differentiation is important because Tr1s potently regulate immune responses by IL-10 production. In this study, we show that costimulation of human naive CD4+ cells through CD97/CD55 interaction drives Tr1 activation, expansion, and function. T cell activation and expansion was equipotent with CD55 or CD28 costimulation; however, CD55 costimulation resulted in two IL-10–secreting populations. Most IL-10 was secreted by the minor Tr1 population (IL-10highIFN-γ−IL-4-, <5% cells) that expresses Tr1 markers CD49b, LAG-3, and CD226. This Tr1 phenotype was not restimulated by CD28. However, on CD55 restimulation, Tr1s proliferated and maintained their differentiated IL-10high phenotype. The Tr1s significantly suppressed effector T cell function in an IL-10–dependent manner. The remaining (>95%) cells adopted a Th1-like IFN-γ+ phenotype. However, in contrast to CD28-derived Th1s, CD55-derived Th1s demonstrated increased plasticity with the ability to coexpress IL-10 when restimulated through CD55 or CD28. These data identify CD55 as a novel costimulator of human Tr1s and support a role for alternative costimulatory pathways in determining the fate of the growing number of T helper populations. This study demonstrates that CD55 acts as a potent costimulator and activator of human naive CD4+ cells, resulting in the differentiation of a discrete Tr1 population that inhibits T cell function in an IL-10–dependent manner and maintains the Tr1 phenotype upon restimulation.

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

“…However, the extent of the inflammation is not as severe as in other EO-IBD patients. The origin of the inflammation is still unclear, but we propose 2 potential pathomechanisms: dysregulation of immunoregulatory T cells, similar to observation made in mouse models on the role of CD55 on T reg homeostasis,169 and epithelial and/or endothelial barrier damage due to complement activation. Interestingly, some patients develop thrombotic events, a clinical manifestation of many complementopathies.…”

The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases

“…generated in vitro can be purified from bulk cultures using CD49b and LAG-3 antibodies (Amodio et al, 2015;Gagliani et al, 2013b;Mfarrej et al, 2017;Petrelli et al, 2015). The frequency of CD4 + CD45RA -CD49b + LAG-3 + cells correlates with the expression of IL-10 in human (Amodio et al, 2015;Mfarrej et al, 2017;Petrelli et al, 2015;Sutavani et al, 2013;Tousa et al, 2017;Yao et al, 2015;Tousa et al, 2017), and with induction of immunological tolerance in different preclinical and clinical settings Gagliani et al, 2013b;Kim et al, 2018;Koch et al, 2015;Zhu et al, 2018). Using single-cell mass cytometry, we have shown that CD49b and LAG-3 were sufficient to identify a population of CD4 + CD45RAcells, which is distinct from Th1, Th2, Th17, Tfh, and Treg cells.…”

Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance

“…20,26,30,31 Third, co-stimulatory molecules such as ICOS ligand (ICOS-L), CD46, CD2, and CD55 are involved in the differentiation of Tr1 cells. 30,[32][33][34] It has also been showed that the long-term interactions of GITR/GITRL signaling boosted Tr1-cell differentiation and expansion in mice in vivo. 35 Zohar et al believed that chemokine (C-X-C motif) ligand 11/chemokine receptor 3 (CXCL11/CXCR3) interaction may induce transformation of CD4…”