TCR-Dependent Cell Response Is Modulated by the Timing of CD43 Engagement

Abstract

Binding of Ag by the Ag receptor in combination with other stimuli provided by costimulatory receptors triggers the expansion and differentiation of T lymphocytes. However, it is unclear whether the time when costimulatory molecules interact with their counterreceptors with regards to Ag recognition leads to different T cell responses. Provided that the coreceptor molecule CD43 is a very abundant molecule evenly distributed on the membrane of T cell surface protruding 45 nm from the cell, we hypothesized that CD43 is one of the first molecules that interacts with the APC and thus modulates TCR activation. We show that engaging CD43 before or simultaneously with the TCR inhibited Lck-Src homology 2 domain containing phosphatase-1 interaction, preventing the onset of a negative feedback loop on TCR signals, favoring high levels of IL-2, cell proliferation, and secretion of proinflammatory cytokines and chemokines. In contrast, the intracellular signals resulting of engaging the TCR before CD43 were insufficient to induce IL-2 production and cell proliferation. Interestingly, when stimulated through the TCR and CD28, cells proliferated vigorously, independent of the order with which molecules were engaged. These results indicate that CD43 induces a signaling cascade that prolongs the duration of TCR signaling and support the temporal summation model for T cell activation. In addition to the strength and duration of intracellular signals, our data underscore temporality with which certain molecules are engaged as yet another mechanism to fine tune T cell signal quality, and ultimately immune function.

CD43 Regulates Th2 Differentiation and Inflammation

“…It remains to be determined how the presence or absence of CD43 on T cells is regulating Th cell differentiation. Studies in human T cells have shown that CD43 costimulation in the presence and absence of TCR stimulation can induce IFN-␥ production and promote Th1 differentiation (42)(43)(44)(45). However, these findings have not been replicated in murine systems, making it unclear whether this plays a role in our model.…”

T Cell Costimulation via the Integrin VLA-4 Inhibits the Actin-Dependent Centralization of Signaling Microclusters Containing the Adaptor SLP-76

“…This enhancement was significantly greater (p < 0.02) than that observed after the coligation of CD43 (2.3 ± 0.3-fold over OKT3 alone, mean ± SEM, n = 5 experiments, p < 0.001; Figure 2E). Because CD43 has been shown to transmit either costimulatory or inhibitory signals in certain model systems, we also measured the NF-AT:AP-1 responses of T cells stimulated in the presence of both anti-CD43 and VCAM-1 ( Figure 2D) (Fierro et al, 2006;Tong et al, 2004). Under our assay Immunity VLA-4 Inhibits Microcluster Translocation conditions, CD43 exhibited no inhibitory effect.…”

Vm24, a Natural Immunosuppressive Peptide, Potently and Selectively Blocks Kv1.3 Potassium Channels of Human T Cells

“…Cells were stimulated with anti-CD3 (OKT3, 100 ng/ml; American Type Culture Collection, Manassas, VA) and anti-CD28 (500 ng/ml; Ancell Corp., Bayport, MN) mAbs at room temperature for 15 min, after which a secondary anti-mouse polyclonal antibody (rabbit anti-mouse immuImmunosuppressive Peptide Toxin from Scorpion Venom 373 at ASPET Journals on May 7, 2018 molpharm.aspetjournals.org noglobulin, 1 g/ml) was added to cross-link the primary antibodies (Fierro et al, 2006). Cells were then incubated at 37°C in 5% CO 2 for the indicated times.…”