Virus infections of the respiratory tract are responsible for a great deal of illness and even death among the world's human population. Influenza, in particular, has the potential to become a deadly pandemic as evidenced by the recent outbreak in Hong Kong in 1997. It is essential to understand how the immune system clears a virus infection and provides long term immunity if we are to design more rational vaccination and treatment strategies. We focus on the virus specific T cells which orchestrate the specific immune response. CD4⁺ T cells provide help for B cells to make antibodies and are important for enhancing the generation of cytotoxic CD8⁺ T cells. The cytotoxic cells can act through either one of two distinct mechanisms to kill the virus infected cell. One mechanism involves the expression of perforin to "poke holes" in the membrane of the infected cell thereby initiating a cytotoxic cascade. In the absence of perforin, death of the infected cell can be induced through a signal delivered by Fas-Ligand on the antiviral CD8⁺ T cells and Fas expressed on the virus infected cell.

Once generated, some antiviral T cells persist for the life of the individual to provide immune memory. Antiviral CD4⁺ T cells were found not only to persist for the life of the animals, yet may increase in number with advanced age. Since immunity appears to diminish as we get older, unraveling this paradox of long term immunity will be important in designing strategies to protect the elderly from dangerous virus infections.

Ray SJ, Franki SN, Pierce RH, Dimitrova S, Koteliansky V, Sprague AG, Doherty PC, de Fougerolles AR, Topham DJ. The collagen binding alpha1beta1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection. Immunity 20:167-79, 2004.

Sangster MY, Riberdy JM, Gonzalez M, Topham DJ, Baumgarth N, Doherty PC. An Early CD4+ T Cell-dependent Immunoglobulin A Response to Influenza Infection in the Absence of Key Cognate T-B Interactions. J. Exp. Med. 198 1011-1021, 2003.

Topham DJ, Crispe IN. Contrasting urban and rural lifestyles of memory CD8+ T cells. Immunity 18:584-6, 2003.

Topham DJ, Castrucci MR, Wingo FS, Belz GT, Doherty PC. The Role of Antigen in the Localization of Naive, Acutely Activated, and Memory CD8(+) T Cells to the Lung During Influenza Pneumonia. J Immunol. 167:6983-6990, 2001.

Topham DJ, Cardin RC, Christensen JP, Brooks JW, Belz GT, Doherty PC. Perforin and Fas in murine gammaherpesvirus-specific CD8(+) T cell control and morbidity. J Gen Virol. 82:1971-81, 2001.

Sangster MY, Topham DJ, D'Costa S, Cardin RD, Marion TN, Myers LK, Doherty PC. Analysis of the virus-specific and nonspecific B cell response to a persistent B-lymphotropic gammaherpesvirus. J Immunol. 164:1820-8, 2000.

Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Pendeville H, Yasukawa H, Sasaki A, Yoshimura A, Ihle JN. SOCS3 is essential in the regulation of fetal liver erythropoiesis. Cell 98:617-27, 1999.

Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN. SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98:609-16, 1999.

Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C, Wang D, Hoffmeyer A, van Deursen J, Sangster MY, Bunting KD, Grosveld GC, Ihle JN. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10:249-59, 1999.

Brown MP, Topham DJ, Sangster MY, Zhao J, Flynn KJ, Surman SL, Woodland DL, Doherty PC, Farr AG, Pattengale PK, Brenner MK. Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nature Medicine 4:1253-60, 1998.

Topham DJ, Doherty PC. Longitudinal analysis of the acute Sendai virus-specific CD4+ T cell response and memory. J Immunol 161:4530-5, 1998.

Topham DJ, Doherty PC. Clearance of an influenza virus by CD4+ T cells is inefficient in the absence of B cells. J Virol 72:882-885, 1998.