A question of self-preservation : immunopathology in influenza virus infection

Influenza A viruses that circulate normally in the human population cause a debilitating, though generally transient, illness that is sometimes fatal, particularly in the elderly. Severe complications arising from pandemic influenza or the highly pathogenic avian H5N1 viruses are often associated with rapid, massive inflammatory cell infiltration, acute respiratory distress, reactive hemophagocytosis and multiple organ involvement. Histological and pathological indicators strongly suggest a key role for an excessive host response in mediating at least some of this pathology. Here, we review the current literature on how various effector arms of the immune system can act deleteriously to initiate or exacerbate pathological damage in this viral pneumonia. Generally, the same immunological factors mediating tissue damage during the anti-influenza immune response are also critical for efficient elimination of virus, thereby posing a significant challenge in the design of harmless yet effective therapeutic strategies for tackling influenza virus.

Differential tumor necrosis factor receptor 2-mediated editing of virus-specific CD8+ effector T cells

Much of the CD8+ T cell response in H2b mice with influenza pneumonia is directed at the nucleoprotein366-374 (NP366) and acid polymerase224-233 (PA224) peptides presented by the H2Db MHC class I glycoprotein. These DbNP366- and DbPA224-specific T cell populations are readily analyzed by staining with tetrameric complexes of MHC+ peptide (tetramers) or by cytokine production subsequent to in vitro stimulation with the cognate peptides. The DbPA224-specific CD8+ effector T cells make more tumor necrosis factor (TNF) α than the comparable CD8+DbNP366+ set, a difference reflected in the greater sensitivity of the CD8+DbPA224+ population to TNF receptor (TNFR) 2-mediated apoptosis under conditions of in vitro culture. Freshly isolated CD8+DbNP366+ and CD8+DbPA224+ T cells from influenza-infected TNFR2-/- mice produce higher levels of IFN-γ and TNF-α after in vitro stimulation with peptide, although the avidity of the T cell receptor-epitope interaction does not change. Increased numbers of both CD8+DbPA224+ and CD8+DbNP366+ T cells were recovered from the lungs (but not the spleens) of secondarily challenged TNFR2-/- mice, a pattern that correlates with the profiles of TNFR expression in the TNFR2+/+ controls. Thus, it seems that TNFR2-mediated editing of influenza-specific CD8+ T cells functions to limit the numbers of effectors that have localized to the site of pathology in the lung but does not modify the size of the less activated responder T cell populations in the spleen. Therefore, the massive difference in magnitude for the secondary, although not the primary, response to these DbNP366 and DbPA224 epitopes cannot be considered to reflect differential TNFR2-mediated T cell editing.