Extralymphatic virus sanctuaries as a consequence of potent T-cell activation

Recher M., et al. 2007. Nat. Med. 13, 1316-1323.

Speaker: Yen-Chun Lin (林妍君)                                            Time: 14:10~15:00, Mar. 12, 2008

Commentator: Dr. Chiou-Feng Lin (林秋峰 老師)                Place: Room 601

Abstract:

    Some viruses are able to escape immune system and cause persistent infection. The sites of virus persistence may be influenced by virus tropism, immune surveillance or drug therapy. They often resist complete elimination and remain detectable at sanctuary sites, such as kidneys, and other extralymphatic organs. In anti-viral immune system, CD4⁺ T cells are known to help cytotoxic T cells to destroy virus-infected cells. However, previous study shown that immunolization with CD4⁺ T cell epitopes would worsen the outcome of simian immunodeficiency virus infection. In addition, T helper cell would suppress neutralizing antibody formation after lymphocytic choriomeningitis virus(LCMV) infection (1). To understand the roles of virus-specific T cell and neutralizing antibody in enhancing or eliminating the chronic virus infection, the authors used LCMV-infected C57BL/6 with transient CD8⁺ T cell depletion to reveal the puzzle. They found that pre-existed naïve, LCMV-specific T cell receptor transgenic CD4⁺ T cell (Smarta cell) would enhance virus-specific CD8⁺ T cell expansion and activation. Nevertheless, C57BL/6 adoptively transferred of Smarta cells (C57BL/6+Smarta) would delay virus clearance due to virus persistence in the kidneys and lungs. This phenomenon may correlate with delayed neutralizing antibody formation while the number and the function of T helper cells were comparable in the spleen, liver, lungs, and kidneys. The same results also could be observed in LCMV-infected Aicda^-/- mice, which had normal B cell and IgM functions but couldn’t undergo class switch and affinity maturation due to activation-induced cytidine deaminase (AID) deficiency. Adoptively transferred of LCMV-specific B cells but not LCMV-specific T cells into Aicda^-/- mice could reduce the viral titer in the kidneys and lungs. Further studies found that although cytotoxic T cells in the kidneys were activated, they were exhausted with low cytotoxicity. Neutralizing IgG could enter the interstitial space of kidneys and then eliminate the virus. In conclusion, although cytotoxic T cells are important in virus clearance, neutralizing antibodies are still needful in organs with tubular epithelial microanatomy such as kidneys and lungs to do the complementary virus elimination.

References:

1.        Recher M. et al. 2004. Deliberate removal of T cell help improves virus-neutralizing antibody production. Nat. Immunol. 5:934-942