ICOS Deficiency Is Associated with a Severe Reduction of CXCR5+CD4 Germinal Center Th Cells

Abstract

ICOS is expressed on activated T cells and particularly on CXCR5+ follicular Th cells in germinal centers (GC). Its deletion leads to a profound deficiency in memory B cell formation and switched Ab response in humans. Here, we show that in ICOS-deficient patients the generation of GCs is severely disturbed, and the numbers of circulating CXCR5+CD45RO+ memory CD4 T cells are significantly reduced, indicating an essential role of ICOS in the differentiation of CXCR5+CD4 T cells. The GC-specific CD57+CXCR5+ subpopulation is virtually absent. In ICOS−/− mice, the decrease of circulating CXCR5+CD4 T cells reflects the reduction of CXCR5+ follicular Th cells in lymph nodes and spleen. Therefore, in concurrence with the absence of CXCR5+ T cells in the blood of CD40L-deficient patients, these data support the hypothesis that circulating CD57+CXCR5+ T cells are GC derived and thus may serve as a surrogate marker for the presence of functional GCs in humans.

Common variable immunodeficiency: Crossroads between infections, inflammation and autoimmunity

“…Defects have been found in the genes that encode for B cell antigen receptor associated complex (CD19, CD81, and CD21) (25 27), CD20 (28), inducible co-stimulator (ICOS) (29), and B cell activating factor receptor (BAFF-R) (30). Nevertheless, taken together, these defects account for less than 3% of patients (31).…”

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…The patients deficient in ICOS and CD40L lack T FHC cells, whereas T FHC cells expressing ICOS are overrepresented in SLE and rheumatoid arthritis patients. 10,51,53 T FH CELLS AND IMMUNODEFICIENCY Immunodeficiency is a pathological condition where the immune response is compromised or absent. Defects in humoural immune response lead to the humoral immunodeficiencies, such as common variable immunodeficiency (CVID), X-linked hyper IgM syndrome (HIGM) and X-linked lymphoproliferative disease (XLP).…”

“…Consistently, ICOS-deficient mice were significantly depleted of CXCR5 1 T FH cells in the blood and lymphoid tissues, and that the lack of GC was associated with reduced numbers of CXCR5 1 T FH cells in B-cell follicles. 10 Furthermore, deletions of CD19 can also cause CVID, which is characterized by defective B-cell responses and lack of T FH cells. 59 Similar to these findings, individuals suffering from XLP and SAP-deficient mice also exhibit severely impaired B-cell responses with altered development and/or function of T FH cells.…”

“…4,5 However, if T FH -cell function is not properly regulated, various pathologies ensue. [6][7][8][9][10][11] Here we present a review of the current literature pertaining to the role of T FH cells in the development of pathologies, such as autoimmunity, immunodeficiency and lymphoma, and the implications of these studies for development of therapies.…”

Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase

“…Both in mice and humans, interruption of ICOS-ICOS-L interaction leads to impaired GC reaction, Ab class switch, and affinity maturation (13)(14)(15)(16). Recent findings suggested that these defects in humoral immune responses in ICOS-deficiency are due to the lack of T FH cells (17)(18)(19). Conversely, dysregulated overexpression of ICOS in sanroque mice causes a lupus-like autoimmune disease that is associated with an increased number of T FH cells, spontaneous GC reaction, and augmented IL-21 production (20)(21)(22).…”