Impaired CD4 and CD8 Effector Function and Decreased Memory T Cell Populations in ICOS-Deficient Patients

Abstract

Interaction of ICOS with its ligand is essential for germinal center formation, T cell immune responses, and development of autoimmune diseases. Human ICOS deficiency has been identified worldwide in nine patients with identical ICOS mutations. In vitro studies of the patients to date have shown only mild T cell defect. In this study, we report an in-depth analysis of T cell function in two siblings with novel ICOS deficiency. The brother displayed mild skin infections and impaired Ig class switching, whereas the sister had more severe symptoms, including immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T cells in both patients showed a decreased percentage of CD4 central and effector memory T cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or PMA/ionophore stimulation. The defective polarization into effector cells was associated with impaired induction of T-bet, GATA3, MAF, and retinoic acid-related orphan nuclear hormone receptor (RORC). Reduced CTLA-4+CD45RO+FoxP3+ regulatory T cells and diminished induction of inhibitory cell surface molecules, including CTLA-4, were also observed in the patients. T cell defect was not restricted to CD4 T cells because reduced memory T cells and impaired IFN-γ production were also noted in CD8 T cells. Further analysis of the patients demonstrated increased induction of receptor activator of NF-κB ligand (RANKL), lack of IFN-γ response, and loss of Itch expression upon activation in the female patient, who had autoimmunity. Our study suggests that extensive T cell dysfunction, decreased memory T cell compartment, and imbalance between effector and regulatory cells in ICOS-deficient patients may underlie their immunodeficiency and/or autoimmunity.

Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation

“…These results also correlate with clinical observations in ICOS-deficient patients, whose CD4 + T cells exhibit normal IL-2 production but reduced secretion of the cytokines IL-4, IFN-γ, IL-10, and IL-17 upon in vitro stimulation, as well as a decreased percentage of CD4 + central and effector memory T cells (32). Interestingly, the percentage of ICOS hi CD4…”

ICOS-Expressing CD4 T Cells Induced via TLR4 in the Nasal Mucosa Are Capable of Inhibiting Experimental Allergic Asthma

“…ICOS deficiency in humans precipitates either immunodeficiency or autoimmunity, indicating its importance in immunoregulation (37). Through adoptive transfer studies, we confirmed that ICOS-expressing CD4 + cells from the cervical LNs of Protollin-treated mice were capable of inhibiting the development of allergic airway disease, indicating that the TLR4-dependent induction of ICOS via the nasal mucosa can inhibit lower airway allergic disease.…”

“…Thus, we hypothesized that nasal application of Protollin would inhibit experimental asthma by promoting Th1 or Treg responses. ICOS is expressed by all of the aforementioned T cell subsets and is important in the differentiation (35), effector (36,37), proliferative (38), migratory (39) and memory (40) functions of T cells. A number of recent reports have shown that ICOS expression on Tregs enhances the function, proliferation and survival of these cells and has critical immunoregulatory implications (41).…”

ICOS-Ligand Expression on Plasmacytoid Dendritic Cells Supports Breast Cancer Progression by Promoting the Accumulation of Immunosuppressive CD4+ T Cells

“…This role of ICOS in TA-Treg biology is supported by the fact that (i) ICOS þ Treg have a stronger suppressive function in melanoma (46) and murine models (27,28), and (ii) ICOS deletion in human (22) and mice (23) correlates to a decreased Treg proportion.…”

“…Identified in 1999 (18), ICOS, a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, plays a nonoverlapping function with CD28 (19) on CD4 þ T cells. In particular, ICOS is critical in the regulation of humoral response (20) through its role on T follicular helper cell activation as illustrated in ICOS KO mice (21) and deficient patients (22). ICOS expression has also been linked with Treg maintenance in mice (23) and mucosal tolerance (24).…”