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

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Abstract
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 α1β1 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 (α1 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-γ–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 α1−/− 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.