Abstract
After infection, extralymphoid tissues are enriched with effector and memory T cells of a highly activated phenotype. The capacity for rapid effector cytokine response from extralymphoid tissue-memory T cells suggests these cells may perform a ‘sentinel’ function in the tissue. While it has been demonstrated that extralymphoid CD4+ T cells can directly respond to secondary infection, little is known about how rapidly this response is initiated, and how early activation of T cells in the tissue may affect the innate response to infection. Here we use a mouse model of secondary heterosubtypic influenza infection to show that CD4+ T cells in the lung airways are reactivated within 24 hours of secondary challenge. Airway CD4+ T cells initiate an inflammatory cytokine and chemokine program that both alters the composition of the early innate response and contributes to the reduction of viral titers in the lung. These results show that, unlike a primary infection, extralymphoid tissue-memory CD4+ T cells respond alongside the innate response during secondary infection, thereby shaping the overall immune profile in the airways. These data provide new insights into the role of extralymphoid CD4+ T cells during secondary immune responses.
Highlights
In recent years it has become clear that extralymphoid tissues play an important role in the adaptive immune response by harboring primed T cells following infection or immunization, many of which have an effector phenotype [1,2,3,4]
We demonstrated that inhibition or deletion of the alpha chain of VLA-1 leads to a substantial loss of immune protection from secondary challenge [13]
Innate responses are altered compared to primary infection, likely due to the local early adaptive response. These results demonstrate the sentinel function of airway memory CD4+ T cells during secondary influenza infection, and suggest that the combined effects of early innate and adaptive tissue responses contribute to secondary immune protection
Summary
In recent years it has become clear that extralymphoid tissues play an important role in the adaptive immune response by harboring primed T cells following infection or immunization, many of which have an effector phenotype [1,2,3,4]. It has been shown that primed T cells can be very cross-reactive between infections, suggesting an even more plausible role for extralymphoid cells in site-specific immune protection [7,8] In support of this model, several recent reports have demonstrated that extralymphoid memory T cells can be reactivated by secondary infection, and contribute to immune protection [9,10,11,12]. We recently described a unique population of tissue-memory CD4+ T cells recovered from the lungs of influenza immune mice [4] These local memory cells could be distinguished from their effector memory counterparts in both function and cell surface phenotype, including the expression of the integrin VLA-1. Given the recent identification of a highly functional VLA-1+ tissue-memory CD4+ T cell subset, and the importance of having memory T cells in the airways in models of secondary influenza challenge, we sought to better understand the in vivo contributions and behavior of these local memory T cells
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