CXCR3 Expression Elevated on Peripheral CD8⁺Lymphocytes from HIV/HCV Coinfected Individuals

Abstract

HIV/HCV coinfected patients tend to develop hepatitis C (HCV)-associated liver disorders. Because the chemokine receptor CXCR3 participates in lymphocyte trafficking during hepatic inflammation, it may participate in the escalated liver disorders of coinfected patients. However, to date, the relative frequency and density of receptor on lymphocytes has not been established. This study compared the CXCR3(+) phenotype under various in vitro conditions between lymphocytes from healthy and coinfected individuals. Peripheral lymphocytes were stimulated with phytohemagluttinin for 0-7 d and phenotypes were determined by flow cytometry. Secreted cytokines were measured in culture supernatants by ELISA. Phenotypic differences were observed between groups. CD4(+)CXCR3(+) frequency between groups was equivalent before and during early activation, but increased only among non-infected individuals during late activation (p<0.001). In contrast, CD8(+)CXCR3(+) frequency was consistently greater (p<0.05) among HIV/HCV patients throughout activation. Among those who were non-infected, CD8(+)CXCR3(+) frequency increased (p=0.002) during late activation. However, CD8(+)CXCR3(+) frequency among HIV/HCV patients increased within 24 h of activation (p=0.008), and was nearly universal by late activation (p<0.001). Both groups elaborated Th-1 cytokine profiles; however, coinfected patients released more inflammatory cytokines (p<0.01) than non-infected individuals. In summary, we demonstrated that CD8(+) lymphocytes from HIV/HCV-infected patients expressed more CXCR3 and showed greater upregulatory ability upon activation. The atypical CXCR3 expression and enhanced Th-1 cytokine elaboration among coinfected patients could potentially stimulate increased lymphocyte migration during hepatic inflammation.

CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt

“…hepatocytes, Kupffer cells, hepatic stellate cells) express these chemokines as a response to cellular injury and stress [20][21][22][23][24][25], suggesting a hepatic release of these chemokines. However, it was also implicated that circulating immune cells might contribute to elevated chemokine levels [23,29]. Our data do not support a distinct place of production or clearance of CXCL9.…”

“…The increased intrahepatic levels of CXCR3 ligands during liver disease are also paralleled by elevated serum levels, as demonstrated in various animal and human studies [8,11,13,14,[16][17][18][19][26][27][28]. Circulating inflammatory cells, in addition to liver resident cells, might contribute to their synthesis and secretion as shown previously [23,29].…”

Increased CD56bright NK cells in HIV-HCV co-infection and HCV mono-infection are associated with distinctive alterations of their phenotype

“…Chemokine receptor CXCR3 and its ligands (particularly IP-10) are associated with a type 1 response and recruit lymphocytes to the liver [ 39 , 40 ]. Kimball et al [ 41 ] have previously demonstrated an increased CXCR3 expression on CD8 + T cells from HIV-HCV co-infected patients as compared to healthy controls. A recent study showed HCV infection to be associated with significantly increased frequency of CXCR3 + CD56 bright NK cells but these cells showed an impaired degranulation and IFN-γ secretion in response to hepatic stellate cells (HSCs) [ 42 ].…”

Chemokine (C‐X‐C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt

“…Liver resident cells are supposed to express these chemokines as a response to cellular injury and their activation (25,34,(38)(39)(40)(41). Besides liver resident cells, circulating immune cells also express high levels of these chemokines when activated (34,42). Therefore systemic inflammation might additionally influence levels of CXCL11.…”