Persistence in Temporary Lung Niches: A Survival Strategy of Lung-Resident Memory CD8(+) T Cells

Takamura, Shiki

CD8 + T cell priming following a respiratory virus infection occurs in the lung-draining mediastinal lymph nodes (MLN) after lung-resident antigen-presenting cells (APCs) have transported viral antigens to that site. Lymph noderesident CD8a + conventional dendritic cells (DCs) that acquire antigens from migrant respiratory DCs were initially thought to be pivotal in the initiation of antiviral CD8 + T cell responses (10) . It has recently become apparent, however, that two subsets of respiratory DCs transport viral antigens from the lung and prime naive CD8 + T cells in the MLN (60) . Moreover, those two DC subsets exhibit distinct T cell stimulatory functions and also regulate the tempo of migration to the MLN upon infection, resulting in the generation of distinct memory CD8 + T cell subsets in both lymphoid and nonlymphoid tissues (11, 35) . In brief, CD103 + respiratory DCs that reside between/below epithelial cells possess the specialized ability to uptake apoptotic cellassociated antigens (e.g., virus-infected cells) and crosspresent them on the MHC class I molecules (20, 43, 46) . Upon infection, migration of antigen-laden CD103 + respiratory DCs to the MLN dominates the early stage of infection (2-4 days) (36, 60) . These CD103 + respiratory DCs express high levels of the costimulatory molecule CD24, which has been decorated with high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) released from dying cells, thereby providing strong stimulatory signals to CD8 + T cells through its ligand, receptor for advanced glycan end-products (RAGE) (61) . CD8 + T cells activated by these CD103 + respiratory DCs proliferate vigorously and become potent effector cells that preferentially home back to the lung to eliminate virally infected cells (36, 52) . Since entry into the peripheral tissues is necessary for subsequent differentiation into CD8 + T RM cells, priming with CD103 + respiratory DCs is potentially the primary factor controlling the development of T RM cells. In contrast, CD11b hi respiratory DCs transport and cross-present viral antigens in the MLN at later time points during the infection (5-7 days) (7, 60, 94) . Those include cells that originally reside in the lung interstitium and new emigrants to the lung in response to inflammation (e.g., monocyte-derived DCs) (35) . CD11b hi respiratory DCs uniquely upregulate CD70, the ligand for CD27, in response, in part, to thymic stromal lymphopoietin (TSLP) secreted by virus-infected lung epithelial cells (136) , and are thus capable of providing costimulatory signals to CD8 + T cells (7) . Several lines of evidence support the notion that CD11b hi respiratory DCs contribute less to antiviral CD8 + T cell immunity than CD103 + respiratory DCs because only the selective loss of CD103 + respiratory DCs leads to a severe reduction in the antigen-specific CD8 + T cell responses (36, 46, 60, 100) . The weaker stimulatory potential of CD11b hi respiratory DCs presumably explains their characteristics: preferential generation of the memory CD8 + T cell population that persists in the secondary lymphoid organs, rather than generation of fully differentiated effector CD8 + T cells (61) . Thus, the distinct functionality of respiratory DC subsets critically impacts the memory CD8 + T cell heterogeneity.