Defective thymopoiesis and poor peripheral homeostatic replenishment of T-helper cells cause T-cell lymphopenia in cirrhosis

Abstract

Background & aims: Depletion of circulating CD4(+) T-helper (Th) lymphocytes, especially naive Th cells, is common in cirrhosis. Little is known about the pathogenetic mechanisms involved in Th-cell depletion in cirrhosis. We investigated the mechanisms involved in circulating Th-cell lymphopenia in cirrhosis.

Methods: Circulating naive and memory Th cells were analyzed by flow cytometry in 60 patients with cirrhosis and 40 sex- and age-matched healthy controls. Thymopoiesis, apoptosis, cell activation, and proliferation were assessed through CD31, annexin-V, HLA-DR and Ki-67 expression, respectively. Lipopolysaccharide (LPS)-binding protein (LBP) and spleen size were measured as indicators of bacterial translocation and splenic pooling, respectively.

Results: Compared to controls, patients showed reduced numbers of Th cells involving a greater depletion of the naive than memory Th-cell compartment (2.7- vs. 1.5-fold, respectively). Recent thymic emigrants were diminished (p < 0.01), and each patient had a lower number of CD31(+) naive Th cells than the matched-control. Spontaneous and induced apoptosis (Annexin-V(+)) of Th cells was increased in patients. Activated (HLA-DR(+)) and proliferating (Ki-67(+)) memory Th cells were increased in patients (p < 0.01), and they directly correlated with plasma LBP (p < 0.05) and negatively with naive Th cells (p < 0.01), respectively. Naive Th cells were inversely correlated (p < 0.01) with their frequencies of apoptosis and of activated memory Th cells, LBP, and spleen size. On multivariate analysis, defective thymic generation of naive Th cells, increased memory Th-cell activation, and splenomegaly were independently associated with Th-cell depletion.

Conclusions: Th-cell immunodeficiency in cirrhosis is explained by a universal defect in thymopoiesis exacerbated by splenic pooling and activation-driven cell-death induced by bacterial translocation.

Keywords: Bacterial translocation; IGF-l; IQR; LBP; LPS; Naive Th cells; PBMCs; PHA; Peripheral homeostatic proliferation; Recent thymic emigrants; T-cell receptor; T-cytotoxic; T-helper; TCR; TNF-α; Tc; Th; Th-cell depletion; insulin-like growth factor-1; interquartile range; lipopolysaccharide; lipopolysaccharide binding protein; mAbs; monoclonal antibodies; peripheral blood mononuclear cells; phytohemagglutinin; tumor necrosis factor-alpha.