Mouse hepatitis viral infection induces an extrathymic differentiation of the specific intrahepatic αβ‐TCR^intermediate LFA‐1^high T‐cell population

Abstract

SUMMARYMouse hepatitis virus type 3 (MHV3), a coronavirus, is an excellent model for the study of thymic and extrathymic T-cell subpopulation disorders induced during viral hepatitis. It was recently reported that, in addition to the intrathymic T-cell differentiation pathway, an extrathymic differentiation pathway of ab-T-cell receptor (TCR) T lymphocytes exists in the liver, and becomes important under pathological situations such as autoimmune diseases, malignancies or hepatic bacterial infections. In the present study, we compared the phenotypes of resident hepatic, splenic or thymic T-cell subpopulations during the acute viral hepatitis induced by MHV3 in susceptible C57BL/6 mice. The number of liver-resident mononuclear cells (MNC ) increased during the viral infection, while cellularity decreased. Single positive (SP) CD4+ cells strongly increased in both the liver and thymus, while double positive (DP) (CD4+CD8+) cells, present in the liver and thymus of mock-infected mice, decreased in C57BL/6 mice during the viral infection. A shift of ab-TCRintermediate T cells toward ab-TCRhigh was evidenced in the liver and thymus of infected mice, but not in the spleen. The few ab-TCRint double negative (DN ) (CD4−CD8−) cells also decreased following viral infection. ab-TCRint or high lymphocytes expressing high levels of leucocyte function antigen-1 (LFA-1) increased in the liver of MHV3-infected mice. In addition, liverresident T cells expressed strongly the CD44 (Pgp-1) activation marker, suggesting that they were either activated or antigen experienced during the viral infection. No significant change in T-cell subpopulations was detected in the spleen, suggesting that MHV3 infection could induce an early in situ differentiation of resident hepatic T cells rather than a recruitment of lymphocytes from peripheral lymphoid organs.

Recovery from Mouse Hepatitis Virus Infection Depends on Recruitment of CD8+ Cells Rather Than Activation of Intrahepatic CD4+αβ−TCRinter or NK-T Cells

“…Numbers of intrahepatic mononuclear cells isolated from YAC-MHV3-infected mice (1.40 Ϯ 0.21 ϫ 10 6 cells/liver) were similar to those of uninfected mice (1.38 Ϯ 0.18 ϫ 10 6 cells/ liver). Moreover, as previouly observed, an increase of intrahepatic mononuclear cells was observed in L2-MHV3-infected mice (3.22 Ϯ 0.45 ϫ 10 6 cells/liver) (P Ͻ 0.001) (21). To verify if splenic and intrahepatic lymphocyte subsets are modified in pathogenic L2-MHV3-or attenuated YAC-MHV3-infected mice, percentages of CD4 ϩ and CD8 ϩ T cells were phenotyped by double immunolabeling.…”

“…We have previously observed that infection of susceptible C57BL/6 mice with the pathogenic L2-MHV3 strain induced an increase in the total number of intrahepatic mononuclear cells (MNC) and in the CD4/ CD8 ratio during acute hepatitis (21). Moreover, the hepatic ␣␤ Ϫ TCR inter LFA-1 high and ␣␤ Ϫ TCR high LFA-1 high cells increased.…”

Therapeutic advantage of anti-VAP-1 over anti-α4 integrin antibody in concanavalin a-induced hepatitis

“…Herein, we provide further evidence that VAP‐1 is a good target to ameliorate the autoimmune‐induced hepatic injury by selectively regulating recruitment of CD4 Th2 but not Th1 lymphocytes. We analyzed the effect of anti‐VAP‐1 therapy for lymphocyte recruitment to the liver using a well‐established Con A‐induced hepatitis model . Con A treatment caused acute liver injury as assessed by increased serum transaminase level as early as 4 hours (data not shown) after intravenous administration and continued until 24 hours.…”

“…Concanavalin A (Con A)‐induced hepatic injury is a well‐established murine experimental model of T‐cell‐mediated autoimmune or viral hepatitis that shares several pathological features with the disease in humans . The Con A model also serves to elucidate mechanisms of infiltration and activation of T cells in the liver that are critical for the development of human autoimmune and viral hepatitis . This injury is associated with both T helper (Th)1 and Th2 cell recruitment which release a large amount of interferon‐gamma (IFN‐γ) and interleukin (IL)‐4, respectively.…”

Evolution of the thymus size in response to physiological and random events throughout life

“…T cell maturation is highly complex, and it is thought that the sequence of differentiation of thymocytes to T cells is controlled by the thymus microenvironment. Precursor T cells originate mainly in the yolk sac at first and then in the liver (during fetal development), subsequently in the bone marrow (after birth), and later in other organs too (in aged individuals) (Adkins, 1991;Aguila et al, 1997;Blom et al, 1998;Huang and Auerbach, 1993;Lamontagne et al, 1997;1998;Lepault and Weissman, 1981;Mackall et al, 1995;Moore and Metcalf, 1970;Poccia et al, 1998;Savagner et al, 1988;Scollay et al, 1986;Toribio et al, 1988). They differentiate from hematopoietic stem cells (HSCs) in the bone marrow, where they undergo several phenotypic transformations to give rise to a number of different cell types, including the lymphoid lineage.…”