The role of lymph flow in regulation of innate immunity

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After an immune stimulation, lymphatic vessels transport antigens, regulatory factors, and cells to the lymph node (LN) to initiate protective immunity. Immune responses in the LN (innate and adaptive immunity) take place in a timely manner, and each step depends on some degree of functional lymphatic vessels. However, the role of lymph in immune regulation is often ignored and thus is poorly understood. The lymph composition rapidly changes after an immune stimulation. Using Staphylococcus aureus (S. aureus) skin infection as an immune stimulation model, we will study how lymph regulates neutrophil migration as an early step of host immune defense in the LN. The long-term goal of our study is to elucidate how lymph regulates innate immune protection in the LN. Afferent lymphatic vessels transport lymph to the LN in a matter of minutes allowing changes in the infected area to reach the LN timely. In the LN, lymph flows along a specialized network called conduits to deliver small molecular weight antigens and regulatory factors to their designated locations in the LN parenchyma efficiently. After immune surveillance, lymph and cells exit the LN via efferent lymphatic vessels. The movement of lymph and cells is finely tuned for optimal immune responses in the LNs. After S. aureus skin infection, neutrophils are the first large population of circulating leukocytes to rapidly infiltrate the infected skin and the draining LN to eliminate the bacteria and prevent their systemic spread. In the first 4 hours post-infection (4hpi), neutrophils predominantly infiltrate the LN from high endothelial venules (HEVs). HEVs are specialized LN blood vessels that allow immune cell homing to the LN in homeostatic status. However, neutrophils rarely enter the LN in homeostasis. How can HEVs in the LN react to skin infection in such a short time frame? In preliminary studies, we have found that blocking afferent lymphatic vessels inhibited neutrophil migration in the LN, but not in the skin area infected by S. aureus. Without lymph flow, bacteria in the LN could not effectively recruit neutrophils. Alternatively, neutrophil migration chemokines, CXCL1 and CXCL2, in the skin were sufficient to recruit neutrophils in the LN. We hypothesize that in the early stage of infection, lymphatic vessels transport bacteria and immune regulatory factors in lymph to the LN, and conduits relay lymph-borne immune regulatory factors to HEVs to direct neutrophil migration. Impaired lymph flow interrupts neutrophil migration in the LN. To test this hypothesis, we will dissect how blocking afferent lymphatic vessels (Aim 1); blocking efferent lymphatic vessels (Aim 2) and changing lymph flow along the conduits (Aim 3) regulate neutrophil migration in the LN. Our research program will reveal fundamental mechanism of how lymph participates in immune regulation in the LN.