CD45 Signals outside of Lipid Rafts to Promote ERK Activation, Synaptic Raft Clustering, and IL-2 Production

Abstract

CD45 is dynamically repositioned within lipid rafts and the immune synapse during T cell activation, although the molecular consequences of CD45 repositioning remain unclear. In this study we examine the role of CD45 membrane compartmentalization in regulating murine T cell activation. We find that raft-localized CD45 antagonizes IL-2 production by opposing processive TCR signals, whereas raft-excluded CD45 promotes ERK-dependent polarized synaptic lipid raft clustering and IL-2 production. We propose that these dual CD45 activities ensure that only robust TCR signals proceed, whereas signals meeting threshold requirements are potentiated. Our findings highlight membrane compartmentalization as a key regulator of CD45 function and elucidate a novel signal transduction pathway by which raft-excluded CD45 positively regulates T cell activation.

TLR4, Ethanol, and Lipid Rafts: A New Mechanism of Ethanol Action with Implications for other Receptor-Mediated Effects

“…isoforms of CD45, as reported by the same investigators (76). It is interesting that CD45 exclusion from raft fractions is required for formation of an immunological synapse and for optimal T cell signaling (77). Taken together, these observations are suggesting a possible role for lipid raft alterations in the effects of EtOH on cellular receptor signaling and await further investigation.…”

The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis

“…However, alternative explanations for the enhancement of TCR signaling by variant CD45RA isoforms should also be considered in particular because recent crystal structure data show that the cytoplasmic CD45 domains probably cannot dimerize (27). The localization of molecules within lipid rafts is crucial for their effects on TCR signaling (28,29). Thus, it will be of interest to determine the distribution of variant CD45RA molecules between raft and nonraft subdomains of the cell membrane.…”

Defective Activation of Protein Kinase C and Ras-ERK Pathways Limits IL-2 Production and Proliferation by CD4+CD25+ Regulatory T Cells

“…Changes in the synaptic localization and lipid raft partitioning of CD45 during T cell activation have been described by several investigators (38 -40). Additionally, Zhang et al (41) have shown that raft-excluded CD45 results in sustained ERK activation, enhanced synaptic raft clustering, and increased IL-2 production by T cells following activation. That the positioned exclusion of CD45 or other phosphatases away from the immunological synapse during T cell activation may be altered in Tregs is an intriguing possibility which should be closely examined in light of a recent report demonstrating that the cross-linking of CD45 on Tregs with specific mAbs could abrogate their suppressive action (42).…”