Identification of a Unique Population of Tissue-Memory CD4+ T Cells in the Airways after Influenza Infection That Is Dependent on the Integrin VLA-1

During the immune response to influenza infection, activated T cells are distributed to both lymphoid and extralymphoid tissues, including the infected airways where direct recognition of viral Ag-bearing cells takes place. The collagen-binding alpha(1)beta(1) integrin VLA-1 is essential for the development of memory CD8(+) T cells in the airways, and although expressed by some CD4(+) T cells, its significance has not been demonstrated. We investigated the role of VLA-1 on virus-specific CD4(+) T cells during and after primary or secondary influenza infection of mice. The proportion of CD4(+) cells expressing CD49a (alpha(1) integrin) was low in all tissues sampled during primary infection but increased in the airways after viral clearance. Furthermore, during the first 24 h of a secondary influenza challenge, the majority of IFN-gamma-secreting effector CD4(+) T cells from the airways was in the CD49a(+) population. Airway CD49a(+)CD4(+) cells also expressed reduced markers of apoptosis compared with CD49a(-) cells, and fewer memory or effector CD4(+) cells could be recovered from airways of alpha(1)(-/-) mice, although lymphoid tissues appeared unaffected. These data suggest VLA-1 expression defines a population of tissue memory CD4(+) T cells that act as rapid effectors upon reinfection, and VLA-1 expression is integral to their accumulation in the airways.