Abstract
Dendritic cells (DCs) that drain the gut and skin are known to favor the establishment of T cell populations that home to the original site of DC-antigen (Ag) encounter by providing soluble “imprinting” signals to T cells in the lymph node (LN). To study the induction of lung T cell-trafficking, we used a protein-adjuvant murine intranasal and intramuscular immunization model to compare in vivo-activated Ag+ DCs in the lung and muscle-draining LNs. Higher frequencies of Ag+ CD11b+ DCs were observed in lung-draining mediastinal LNs (MedLN) compared to muscle-draining inguinal LNs (ILN). Ag+ CD11b+ MedLN DCs were qualitatively superior at priming CD4+ T cells, which then expressed CD49a and CXCR3, and preferentially trafficked into the lung parenchyma. CD11b+ DCs from the MedLN expressed higher levels of surface podoplanin, Trem4, GL7, and the known co-stimulatory molecules CD80, CD86, and CD24. Blockade of specific MedLN DC molecules or the use of sorted DC and T cell co-cultures demonstrated that DC surface phenotype influences the ability to prime T cells that then home to the lung. Thus, the density of dLN Ag+ DCs, and DC surface molecule signatures are factors that can influence the output and differentiation of lung-homing CD4+ T cells.
Highlights
Protection against major human respiratory pathogens, such as Mycobacterium tuberculosis (MTB), Bordetella pertussis or influenza viruses would benefit from the persistence of lung effector T cells and/or the rapid reactivation of lung resident memory T cells
CD11b+ Dendritic cells (DCs) comprised of similar proportions of total DCs in both draining lymph node (dLN) sites, whereas the CD103+ subset represented higher, and the double negative (DN) subset represented lower frequencies in the mediastinal lymph node (LN) (MedLN) compared to the inguinal LNs (ILN) (Figure 1B) of immunized mice
There were higher percentages of Ag+ CD11b+ and CD103+ DCs in the MedLN compared to the ILN (Figure 1C), because of the differing total numbers of DC subsets per ILN and MedLN, the absolute number of OVA+ CD11b+ DCs was similar between sites, and the absolute number of OVA+ CD103+ DCs was higher in the MedLN (Figures S1C,D)
Summary
Protection against major human respiratory pathogens, such as Mycobacterium tuberculosis (MTB), Bordetella pertussis or influenza viruses would benefit from the persistence of lung effector T cells and/or the rapid reactivation of lung resident memory T cells. The CXCR3-CXCL10 (IP-10) axis appears critical for the recruitment of pulmonary CD8+ T cells that control the infection [16]. MTB infection or immunization can induce protective CXCR3+ CD4+ T cells that readily enter the lung parenchyma [17, 18]. CD49a appears to allow more selective trafficking into respiratory and reproductive tissues [3, 6], supporting an important role for adhesion molecules in the control of tissue tropism [11]. CD49a has been described to play a role in lung tissue retention in humans, alongside other molecules, such as CD69 [12]
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