Chemoattractant Receptors and Lymphocyte Egress from Extralymphoid Tissue: Changing Requirements during the Course of Inflammation

Abstract

Memory/effector T cells traffic efficiently through extralymphoid tissues, entering from the blood and leaving via the afferent lymph. During inflammation, T cell traffic into the affected tissue dramatically increases; however, the dynamics and mechanisms of T cell exit from inflamed tissues are poorly characterized. Here we show, using both a mouse and a sheep model, that large numbers of lymphocytes leave the chronically inflamed skin. Many T cells capable of producing IFN-γ and IL-17 also entered the draining afferent lymph, demonstrating that memory/effector T cells egress from sites of inflammation. Whereas efficient egress from acutely inflamed skin required lymphocyte-expressed CCR7, chronic inflammation promoted significant CCR7-independent exit as well. Lymphocyte exit at late time points of inflammation was sensitive to pertussis toxin but only partially affected by the drug FTY720, implying the contribution of alternative chemoattractant receptors other than S1P1. Our data show that CCR7 is an important receptor for lymphocyte egress from both resting and inflamed extralymphoid tissues, but that alternative exit receptors come into play during chronic inflammation.

Neutrophils Exhibit Differential Requirements for Homing Molecules in Their Lymphatic and Blood Trafficking into Draining Lymph Nodes

“…The fact that transferred neutrophils cannot access poLNs in the absence of an inflammatory state matches our previous observations in which neutrophil influx was absent in nonimmunized mice (12). This is well in line with the fact that neutrophils are largely excluded from LNs in steady-state conditions, and that chronic inflammation induced by vigorous immunization causes LN hypertrophy and enhancement of leukocyte trafficking (30). It was demonstrated that CFA immunization provokes the expansion of the lymphatic network within and around LNs, and that during LN activation, HEVs undergo a process of growth and remodeling, thus permitting increased cell mobilization from blood and from the tissue that drains to those LNs (31, 32).…”

Lymphatic vessels and tertiary lymphoid organs

“…These data suggest that lymphocyte trafficking through LVs in TLOs in NOD mice occurs under the control of the lymph S1P gradient and re-expression of its receptor by T cells, as occurs in LNs. These data are also consistent with the observation that FTY720 also prevents egress from inflamed tissues into afferent lymphatics (55,56) and raise the exciting possibility that inhibitors of LV function could prevent diabetes and other autoimmune diseases systemically by preventing trafficking from the TLO to the LNs. It is not known whether the LVs in TLOs produce S1P as they do in the rest of the body (4).…”

γδ T Cell Homing to Skin and Migration to Skin-Draining Lymph Nodes Is CCR7 Independent

“…It is possible that high CD62L expression is involved in the CCR7-independent tissue egress (29) and migratory behavior (30,31) of gd T cells, likely in conjunction with other, yet undefined, chemokine receptors. Tissue egress of Th1 cells involving alternative exit receptors has been described in mice with chronic skin inflammation recently (32).…”