Lung Lymphocytes Proliferate Minimally in the Murine Pulmonary Immune Response to Intratracheal Sheep Erythrocytes

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The requirement for urokinase plasminogen activator (uPA) and uPA receptor (uPAR) in T lymphocyte migration is unknown. uPA−/− mice have fewer pulmonary lymphocytes in response to certain infections, but its unknown whether this is due to diminished recruitment. Primed, recipient mice were IT inoculated with Ag. Three days later, fluorescently labeled lymphoblasts from background-matched control wild-type (WT), uPA−/−, or uPAR−/− donor mice were injected i.v., and their recruitment was determined. Approximately twice the number of uPA−/− compared with WT lymphoblasts were recruited to the lungs of WT recipients. This difference was eliminated when uPA−/− and WT lymphoblasts were injected into uPA−/− recipients. Thus, the reduced number of lung lymphocytes in infected uPA−/− mice is not due to reduced recruitment. However, uPAR is critically involved in recruitment. Markedly fewer uPAR−/− compared with WT lymphoblasts were recruited to the lung. These findings suggest that uPAR may be a novel target for immune modulation in T lymphocyte-mediated disorders.

Section: Resultsmentioning

confidence: 99%

Cutting Edge: Antigen-Driven Lymphocyte Recruitment to the Lung Is Diminished in the Absence of Urokinase-Type Plasminogen Activator (uPA) Receptor, but Is Independent of uPA

Gyetko

Sud

Sonstein

et al. 2001

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“…Although priming does not involve adjuvants, initial i.t. challenge induces a predominately type 2 cytokine response with prominent lung eosinophilia (17,26). Repeated i.t.…”

Section: Discussionmentioning

confidence: 99%

“…The absolute lymphocyte count in each specimen was calculated from the white blood cell count and morphologic differential count. The white blood cell counts were performed with a hemocytometer as previously described (26). Morphologic differential counts of the granulocytes, monocytes/macrophages, and lymphocytes in each specimen were performed on stained filter preparations as previously described (24).…”

Section: Flow Cytometry Analysis and Determination Of Absolute Lymphomentioning

confidence: 99%

“…This conclusion is based on the high rate of lymphocyte elimination by in situ apoptosis (50), the very low rate of in situ proliferation (26), and direct evidence that circulating T lymphoblasts are trafficking into the lung throughout the immune response (16). Furthermore, previous experiments in this model indicated that systemic depletion of CD4 ϩ T cells before i.t.…”

Section: Figurementioning

confidence: 99%

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Subset-Specific Reductions in Lung Lymphocyte Accumulation Following Intratracheal Antigen Challenge in Endothelial Selectin-Deficient Mice

Curtis

Sonstein²,

Craig

et al. 2002

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We previously demonstrated induction and expression of CD62E and CD62P in the lungs of mice primed and then challenged with intratracheal (i.t.) SRBC. The current study examined accumulation of endogenous lymphocytes in the lungs of endothelial E- and P-selectin-deficient (E−P−) mice after i.t. SRBC challenge. Compared with syngeneic wild-type (wt) mice, E−P− mice showed an 85–95% decrease in CD8+ T cells and B cells in the lungs at both early and late time points. In contrast, CD4+ T cell accumulation was reduced by ∼60% early, but equivalent to wt levels later. Surprisingly, many γδ T cells were found in lungs and blood of E−P− mice but were undetectable in the lungs and blood of wt mice. Absolute numbers of peripheral blood CD4, CD8, and B lymphocytes in E−P− mice equaled or exceeded the levels in wt mice, particularly after challenge. Trafficking studies using αβ T lymphoblasts confirmed that the recruitment of circulating cells after challenge was markedly reduced in E−P− mice. Furthermore, Ag priming occurred normally in both the selectin-deficient and wt mice, because primed lymphocytes from both groups transferred Ag sensitivity into naive wt mice. Lung production of mRNA for six CC and two CXC chemokines after challenge was equivalent by RT-PCR analysis in wt and E−P− mice. Therefore, reduced lung accumulation of αβ T cells and B cells in E−P− mice did not result from reduced delivery of circulating lymphocytes to the lungs, unsuccessful Ag priming, or defective pulmonary chemokine production. Selectin-dependent lymphocyte recruitment into the lungs following i.t.-SRBC challenge is subset specific and time dependent.

“…Normal lungs contain a large fraction of the body's total lymphocytes, primarily as single cells within alveolar capillaries and walls (50,51). Lung lymphocytes are highly enriched for activated T cells (27,(52)(53)(54), many of which appear not to ever leave the lungs (55). Thus, the observed deficiency in phagocytosis of apoptotic lymphocytes by AM is even more surprising.…”

Section: Discussionmentioning

confidence: 99%

Deficient In Vitro and In Vivo Phagocytosis of Apoptotic T Cells by Resident Murine Alveolar Macrophages

Sonstein

Christensen

et al. 2000

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Apoptotic lymphocytes are readily identified in murine lungs, both during the response to particulate Ag and in normal mice. Because apoptotic lymphocytes are seldom detected in other organs, we hypothesized that alveolar macrophages (AMφ) clear apoptotic lymphocytes poorly. To test this hypothesis, we compared in vitro phagocytosis of apoptotic thymocytes by resident AMφ and peritoneal macrophages (PMφ) from normal C57BL/6 mice. AMφ were deficient relative to PMφ both in percentage containing apoptotic thymocytes (19.1 ± 1% vs 96 ± 2.6% positive) and in phagocytic index (0.23 ± 0.02 vs 4.2 ± 0.67). This deficiency was not due to kinetic differences, was seen with six other inbred mouse strains, and was not observed using carboxylate-modified polystyrene microbeads. Annexin V blockade indicated that both Mφ types cleared apoptotic T cells by a mechanism involving phosphatidylserine expression. By contrast, neither mAb blockade of a variety of receptors (CD11b, CD29, CD51, and CD61) known to be involved in clearance of apoptotic cells, nor the tetrapeptide RGDS (arginine-glycine-aspartic acid-serine) blocked ingestion by either type of macrophage. To confirm these studies, apoptotic thymocytes were given intratracheally or i.p. to normal mice, and then AMφ or PMφ were recovered 30–240 min later. Ingestion of apoptotic thymocytes by AMφ in vivo was significantly decreased at all times. Defective ingestion of apoptotic lymphocytes may preserve AMφ capacity to produce proinflammatory cytokines in host defense, but could contribute to development of autoimmunity by failing to eliminate nucleosomes.