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

Much of the CD8 ⁺ T cell response in H2 ^b mice with influenza pneumonia is directed at the nucleoprotein _366-374 (NP ₃₆₆ ) and acid polymerase _224-233 (PA ₂₂₄ ) peptides presented by the H2D ^b MHC class I glycoprotein. These D ^b NP ₃₆₆ - and D ^b PA ₂₂₄ -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 D ^b PA ₂₂₄ -specific CD8 ⁺ effector T cells make more tumor necrosis factor (TNF) α than the comparable CD8 ⁺ D ^b NP ₃₆₆ ⁺ set, a difference reflected in the greater sensitivity of the CD8 ⁺ D ^b PA ₂₂₄ ⁺ population to TNF receptor (TNFR) 2-mediated apoptosis under conditions of in vitro culture. Freshly isolated CD8 ⁺ D ^b NP ₃₆₆ ⁺ and CD8 ⁺ D ^b PA ₂₂₄ ⁺ 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 ⁺ D ^b PA ₂₂₄ ⁺ and CD8 ⁺ D ^b NP ₃₆₆ ⁺ 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 influenzaspecific 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 D ^b NP ₃₆₆ and D ^b PA ₂₂₄ epitopes cannot be considered to reflect differential TNFR2-mediated T cell editing.