Primary viral infections of the lung induce potent effector CD8 T cell responses. To function in the influenza-infected airways, CD8 T cells must be able to resist cell death. The majority of the CD8 T cells in the airways and lung parenchyma expressed CD49a, the alpha-chain of the type IV collagen receptor VLA-1, and these cells were highly activated, producing both IFN-gamma and TNF-alpha. In the airways, where type IV collagen is abundant, but not the spleen, the CD49a(+) CD8 cells had reduced proportions of annexin V and caspase 8, and >80% expressed the TNF-alpha receptor II, while Fas, TNFR-I, and CD27 expression were similar to CD49a(-) cells. Furthermore, the CD49a(+), but not CD49a(-), CD8 T cells from the airways were resistant to active induction of apoptosis in the presence of type IV collagen and TNF-alpha in vitro. We propose that TNFR-II and the VLA-1 synergize to protect effector CD8 T cells in the infected airways from apoptosis during the acute infection.