A common feature of many infections is that many pathogen-specific memory T cells become established in diverse nonlymphoid tissues. A mechanism that promotes the retention and survival of the memory T cells in diverse tissues has not been described. Our studies show that the collagen binding alpha1beta1 integrin, VLA-1, is expressed by the majority of influenza-specific CD8 T cells recovered from nonlymphoid tissues during both the acute and memory phases of the response. Antibody treatment or genetic deficiency of VLA-1 decreased virus-specific CTL in the lung and other nonlymphoid tissues, and increased them in the spleen. In spite of the increase in the spleen, secondary heterosubtypic immunity against flu was compromised. This suggests that VLA-1 is responsible for retaining protective memory CD8 T cells in the lung and other tissues via attachment to the extracellular matrix.

Most viral infections occur in extralymphoid tissues, yet the mechanisms that regulate lymphocytes in these environments are poorly understood. One feature common to many extralymphoid environments is an abundance of extracellular matrix. We have studied the expression of two members of the β1 integrin family of collagen-binding receptors, α1β1 and α2β1 (CD49a, VLA-1 and CD49b, VLA-2, respectively), on CD4 and CD8 T cells during the response to influenza infection in the lung. Flow cytometry showed that whereas T cells infiltrating the lung and airways can express both CD49a and CD49b, CD49a expression was most strongly associated with the CD8+ subset. Conversely, though fewer CD4+ T cells expressed CD49a, most CD4+ cells in the lung tissue or airways expressed CD49b. This reciprocal pattern suggested that CD4 and CD8 T cells might localize differently within the lung tissue and this was supported by immunofluorescent analysis. CD8+ cells tended to localize in close proximity to the collagen IV-rich basement membranes of either the airways or blood vessels, whereas CD4+ cells tended to localize in the collagen I-rich interstitial spaces, with few in the airways. These observations suggest that CD4 T cell interaction with the tissue microenvironment is distinct from CD8 T cells and support the concept that CD4+ T cells in peripheral tissues are regulated differently than the CD8 subset.