The Functional Paradox of CD43 in Leukocyte Recruitment: A Study Using CD43-deficient Mice

Woodman, Richard C.; Johnston, Brent; Hickey, Michael J.; Teoh, Diane; Reinhardt, Paul H.; Poon, Betty Y.; Kubes, Paul

doi:10.1084/jem.188.11.2181

Cited by 87 publications

(74 citation statements)

References 33 publications

(44 reference statements)

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“…These data, along with previously published studies, point toward a leukocyte subset-specific repertoire of ligands for E-selectin: whereas PSGL-1 and CD44 appear to contribute to binding activity in both myeloid and T lymphocytes ( 6,10,11 and the present study), the activity of CD43 appears to be restricted to T lymphocytes 5,7,45 and that of ESL-1 likely to neutrophils. 7,11 Moreover, our studies suggest that each of these ligands makes a specialized contribution to the different steps of leukocyte recruitment: both PSGL-1 and CD43 localize to the microvillus projections 46,47 and are therefore more suitable to mediate tethering and initial rolling interactions.…”

Section: Discussionsupporting

confidence: 50%

Physiological Contribution of CD44 as a Ligand for E-Selectin during Inflammatory T-Cell Recruitment

Nácher

Blázquez

Shao

et al. 2011

The American Journal of Pathology

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Endothelial selectins guide the migration of inflammatory T cells to extralymphoid tissues. Whereas Pselectin glycoprotein ligand-1 (PSGL-1) functions as the exclusive ligand for P-selectin, it acts in coordination with additional glycoproteins to mediate Eselectin binding. CD44 can act as one such ligand in neutrophils, but its contribution in inflammatory T lymphocytes remains unexplored. We have used realtime in vivo imaging of the cremasteric and dermal microcirculations to explore the dynamics of leukocyte recruitment, as well as the physiological contribution of CD44 in a model of Th1-driven inflammation. CD4؉ T-cell rolling frequency and kinetics, as well as arrest, were dependent on endothelial selectins and were markedly altered under inflammatory conditions. CD44 extracted from Th1 cells bound to soluble E-selectin in vitro and cooperated with PSGL-1 by controlling rolling velocities and promoting firm arrest. Using several competitive recruitment assays in a delayed-type hypersensitivity model, we show that the combined absence of CD44 and PSGL-1 impairs inflammatory T-cell recruitment beyond that of PSGL-1 alone. Differential expression of leukocyte fucosyltransferases in these cells may account for the differential use of E-selectin ligands relative to neutrophils. Our results identify additional mechanisms by which CD44 modulates the inflammatory response. The trafficking of T lymphocytes is regulated by their repertoire of adhesion and chemotactic receptors. Naïve T cells recirculate through secondary lymphoid organs in search of their cognate antigen, a process facilitated by their specific binding to high endothelial venules through L-selectin, ␤2 integrins, and the chemokine receptor CCR7. Once activated, effector and memory T cells switch their adhesive and signaling repertoire to one that allows immune surveillance of tissues. In particular, skin and inflamed areas are dynamically infiltrated by activated T cells, a process that underlies a number of pathogenic inflammatory diseases.1 It is generally accepted that this infiltration is initiated by extravasation from the blood microvasculature through a multistep cascade similar to that undergone by neutrophils, including initial tethering and rolling events followed by firm arrest and diapedesis.2 Tethering and rolling are initiated by labile interactions mediated by endothelial P-and E-selectins (encoded by Selp and Sele genes, respectively) expressed constitutively in the skin microvasculature 3 and induced in other tissues during inflammation.2 Induction of ligands for endothelial selectins is therefore critical for the acquired migrating properties of inflammatory lymphocytes. 4 Two glycoproteins expressed on Th1 lymphocytes, Pselecting glycoprotein ligand-1 (PSGL-1; encoded by Selplg) and the sialomucin CD43, have been shown to

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Section: Discussionsupporting

confidence: 50%

Physiological Contribution of CD44 as a Ligand for E-Selectin during Inflammatory T-Cell Recruitment

Nácher

Blázquez

Shao

et al. 2011

The American Journal of Pathology

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“…Early studies documented both positive and negative regulatory roles for CD43 in T cell activation (17)(18)(19), however these results may be reconciled by a recent report suggesting that CD43 plays a dynamic role in the progression of an immune response (12). Although earlier studies described a negative regulatory role for CD43 on T cell adhesion (18,20), more recent studies have demonstrated a positive role for CD43 in T cell homing to secondary lymphoid organs and peripheral tissues (21)(22)(23). For example, anti-CD43 mAbs have been shown to prevent the migration of T cells to pancreatic islets and thereby prevent the development of diabetes in a nonobese diabetic model (23).…”

mentioning

confidence: 46%

CD43 Modulates Severity and Onset of Experimental Autoimmune Encephalomyelitis

Ford

Onami

Sperling

et al. 2003

The Journal of Immunology

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Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis characterized by infiltration of activated CD4+ T lymphocytes into tissues of the CNS. This study investigated the role of CD43 in the induction and progression of EAE. Results demonstrate that CD43-deficient mice have reduced and delayed clinical and histological disease severity relative to CD43+/+ mice. This reduction was characterized by decreased CD4+ T cell infiltration of the CNS of CD43−/− mice but similar numbers of Ag-specific T cells in the periphery, suggesting a defect in T cell trafficking to the CNS. The absence of CD43 also affected cytokine production, as myelin oligodendrocyte glycoprotein (MOG) 35–55-specific CD43−/− CD4+ T cells exhibited reduced IFN-γ and increased IL-4 production. CD43−/− CD4+ MOG-primed T cells exhibited reduced encephalitogenicity relative to CD43+/+ cells upon adoptive transfer into naive recipients. These results suggest a role for CD43 in the differentiation and migration of MOG35–55-specific T cells in EAE, and identify it as a potential target for therapeutic intervention.

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“…CD43 has been shown to play a role in the trafficking of T cells and monocytes to sites of inflammation (10,11). However, it is also purported to play an antiadhesive role in lymphocyte trafficking, suggesting increased trafficking of lymphocytes to some tissues in PFU LCMV-Armstrong i.c.…”

Section: Role For Cd43 In Trafficking Of Cd8 T Cells To Tissuesmentioning

confidence: 99%

Dynamic Regulation of T Cell Immunity by CD43

Onami

Harrington

Williams³

et al. 2002

The Journal of Immunology

105

131

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During a viral response, Ag-specific effector T cells show dramatically increased binding by the mAb 1B11 and the lectin peanut agglutinin (PNA). We investigated the contribution of CD43 expression to 1B11 and PNA binding as well as its role in generation and maintenance of a CD8 T cell response. Analysis of CD43−/− mice revealed no increased 1B11 binding and reduced PNA binding on virus-specific CD8 T cells from −/− mice compared with +/+ mice. Furthermore, we examined the role of CD43 in the kinetics of an immune response. We show that CD43 expression modestly effects generation of a primary virus-specific CD8 T cell response in vivo but plays a more significant role in trafficking of CD8 T cells to tissues such as the brain. More interestingly, CD43 plays a role in the contraction of the immune response, with CD43−/− mice showing increased numbers of Ag-specific CD8 T cells following initial expansion. Following the peak of expansion, Ag-specific CD8 T cells from −/− mice show similar proliferation but demonstrate increased Bcl-2 levels and decreased apoptosis of Ag-specific effector CD8 T cells in vitro. Consistent with a delay in the down-modulation of the immune response, following chronic viral infection CD43−/− mice show increased morbidity. These data suggest a dynamic role of CD43 during an immune response: a positive regulatory role in costimulation and trafficking of T cells to the CNS and a negative regulatory role in the down-modulation of an immune response.

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The Functional Paradox of CD43 in Leukocyte Recruitment: A Study Using CD43-deficient Mice

Cited by 87 publications

References 33 publications

Physiological Contribution of CD44 as a Ligand for E-Selectin during Inflammatory T-Cell Recruitment

Physiological Contribution of CD44 as a Ligand for E-Selectin during Inflammatory T-Cell Recruitment

CD43 Modulates Severity and Onset of Experimental Autoimmune Encephalomyelitis

Dynamic Regulation of T Cell Immunity by CD43

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