Altered Responses to Homeostatic Cytokines in Patients with Idiopathic CD4 Lymphocytopenia

Abstract

Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4+ T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4+ T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4+ T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4+ T cells of some ICL patients, which correlated with a decreased expression of the IL-7Rα receptor chain (R = 0.74, p<0.005) and with lower CD4+ T cell counts (R = 0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R = 0.75, p<0.005), pointing to combined defects that may significantly perturb CD4+ T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R = −0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4+ T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in γc cytokine responses.

A Panoply of Rheumatological Manifestations in Patients with GATA2 Deficiency

“…Specifically, we observed that patients with GATA2 deficiency and rheumatological manifestations have decreased CD4+ helper T cell proportions and a decreased naïve helper T cell sub-compartment. These results are consonant with findings in patients with idiopathic CD4 lymphocytopenia, who also have decreased naïve helper T cells 24 .…”

DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia

“…3,11,12 ICL might result from defective thymic production or output of T cells, exacerbated peripheral consumption, or any combination of these. [4][5][6][12][13][14][15][16][17][18] Cell-intrinsic or cell-extrinsic factors have been identified in ICL that may participate in the perturbation of CD4 1 T-cell homeostasis. These include altered responses to homeostatic cytokines, such as interleukin-2 (IL-2), IL-7, and CXC chemokine ligand 12, 12,15,16 and an enhanced susceptibility of ICL-derived T cells to undergo apoptosis.…”

Acute Respiratory Failure in Idiopathic Pulmonary Fibrosis: Co-Infection With H1n1 And Cytomegalovirus: An Unexpected Common Denominator

“…The most typical manifestations of ICL are cryptococcal, mycobacterial and other opportunistic infections, malignancies, and autoimmune disorders. These conditions are all believed to result from immune deregulation [4,5]. Infection with CMV is also described in these patients.…”

“…In this patient, the de novo identification of influenza A H1N1 virus accompanied by the identification of CMV virus indicates that these viruses might have played a role in the acute respiratory failure of this patient [1][2][3]. The H1N1 infection had been treated previously with oseltamivir, and its de novo identification was interpreted as persistence of H1N1, especially in the setting of an idiopathic CD4+ T cell lymphocytopenia (ICL) [4,5]. We measured the CD4+ cells twice in one-week interval.…”