A Role for Interleukin-12 in the Regulation of T Cell Plasma Membrane Compartmentation

Abstract

The immunological synapse initiates the clustering and stabilization of the T cell receptor by the formation of a large lipid microdomain that accumulates (e.g. CD4/ CD8) and segregates (e.g. CD45 and LFA-1) some proteins of the T cell plasma membrane. This work shows that a fraction of transmembrane glycoproteins CD26 and CD45 (the R0 isoform in particular) is present in the rafts of fresh and activated human T lymphocytes. CD26 is proposed as the costimulator of TCR-dependent activation, and CD45 is essential to the T cell activation process because it dephosphorylates at least the inhibitory site of Src kinases. These findings support a more complex model of compartmentation, depending on the stage of T cell maturation and post-transcriptional and post-translational regulation. In addition, interleukin 12 (IL-12; inducer of T H 1 responses) drives CD26 and CD45R0 to particular microdomains, thereby involving interleukins in the rules governing raft inclusion or exclusion. The physical association of CD26 and CD45R0 has long been reported. The results presented in this work fit a model in which IL-12 up-regulates a certain type of CD26 expression that interacts on the cell surface with CD45R0, near but outside of the raft core. The use of antisense oligonucleotides for the CD26 mRNAs demonstrated that both events (enhanced by IL-12), CD26-CD45R0 association and membrane compartment redistribution, are related. Thus, CD26 could be part of a shuttling mechanism for CD45 that regulates membrane tyrosine-phosphatase activities, e.g. to control IL-12 receptor-dependent signal transduction.In the early events of T cell activation, antigen (Ag) 1 presentation results in the clustering of protein-tyrosine kinases, which associate with the CD3 and TCR subunits and the coreceptors CD4 or CD8 (1). The transmembrane tyrosine-phosphatase CD45 is essential in this process because it dephosphorylates at least the inhibitory site of Src family kinases, responsible for the phosphorylation of ITAMs (immunoreceptor tyrosine-based activation motifs) (2). This extremely active phosphatase does not require ligand binding for optimum catalytic activity; later in the process, CD45-dependent dephosphorylation of key substrates, Src, or other protein-tyrosine kinases (e.g. ZAP-70/Syk) and ITAMs must be avoided.An advance in the understanding of CD45 function was the discovery of specialized membrane domains, called rafts, ganglioside-enriched membranes (GEMs), or detergent-resistant membranes (DRMs). These membranes contain a high density of sphingolipids and cholesterol (2-4) and serve as attachment sites for a variety of lipid-modified proteins (including GPI) and also integral membrane and cytoplasmic proteins (e.g. Src family kinases Lck and Fyn, CD4, CD8, and LAT (linker for activation of T cells)). A compartmentation model has been proposed in which the immunological synapse initiates the clustering and stabilization of the TCR by the formation of a large lipid microdomain that accumulates (e.g. CD4 and CD8) and segregates (e.g. ...

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

“…DPP4/ CD26 is involved in T cell activation, T cell signalling and T cell differentiation due to its interactions with ADA, CD45, caveolin-1, CARMA-1 and M6P/IGFII-R [9]. These processes are regulated by the cytokines IL-2, IL-6, IL-10, IL-12, IL-17, IL-29, IFN-g and TGF-b, as well as compartmentation of DPP4/CD26 to either lipid rafts or internalization [8,9,48,88,89,[91][92][93]. Furthermore, post-translation modification of DPP4/CD26 such as sialylation also appears to influence compartmentation and/or the interactions with its binding partners [9,86,87,90].…”

HIV-1 Tat Enters T Cells Using Coated Pits before Translocating from Acidified Endosomes and Eliciting Biological Responses

“…The behavior of CXCR4 appears more complex because it can be found within both coated pits (Signoret et al, 1997) and detergentresistant plasma membrane domains (rafts; Nguyen and Taub, 2002). A fraction of cell-surface CD26 is also found within rafts (Salgado et al, 2003). Because a raft-mediated, clathrin-independent endocytosis pathway exists in T lym- phocytes (Lamaze et al, 2001), the identified receptors could drive Tat endocytosis through either a clathrin-dependent or a raft-mediated pathway, and the initial Tat uptake pathway in T cells remains to be identified.…”

On the role of CD26 in CD4 memory T cells

“…CD26 can act in three ways; through its binding to the ADA ectoenzyme (in humans and other mammals but not in mice), through its enzymatic activity, and through other transient protein-protein interactions (Fleischer, 1994;Franco et al, 1998;Morimoto and Schlossman, 1998;De Meester et al, 1999;Hildebrandt et al, 2000). Focusing on the T cells, complexity increases when we look at its regulation, since CD26 gene expression is both developmentally regulated and inducible following T cell activation, particularly when observed at the posttranslational level (translocation to the cell surface and glycosylation) (Hafler et al, 1986;Morimoto et al, 1989;Dang et al, 1991;Mattern et al, 1995;Amlot et al, 1996;Cordero et al, 1997;Yawalkar et al, 2000;Salgado et al, 2000Salgado et al, , 2003Boonacker et al, 2002).…”

“…We previously described the anti-CD26 mAb TA1/16 (Salgado et al, 2000(Salgado et al, , 2003 and recently used this mAb to further subdivide CD4 T cells as follows (unpublished data): CD45R0 bright CD26 + T cells (which included a very small CD26 bright population), CD45R0 weak CD26 + , CD45R0 À CD26 + and CD45R0 À CD26 À populations. CD26 was expressed on the whole population of CD4 + CD8 + medullary thymocytes and highly expressed (90% were CD26 + ) on human cord blood T cells (which were almost entirely CD45RA + ).…”