Potentiation of T Cell Function by a Marine Algae-Derived Sulfated Polymannuroguluronate: In Vitro Analysis of Novel Mechanisms

Abstract

Abstract. Marine algae-derived sulfated polymannuroguluronate (SPMG), a candidate drug for AIDS treatment, was intraperitoneally injected into normal mice for 6 weeks, and the in vivo and in vitro mechanisms of SPMG for immunomodulation were investigated in isolated lymphocytes by MTT assay, flow cytometry, and surface plasmon resonance assay. SPMG treatment at 5 and 10 mg / kg enhanced concanavalin A (ConA)-induced T cell proliferation, cellular levels of CD69, interleukin-2 (IL-2), and interferon-g (IFN-g), as well as CD4/ CD8 ratio, while decreasing tumor necrosis factor-a (TNF-a ) level in T cells of peripheral blood mononuclear cells. In addition, 1 molecule of SPMG bound to 2 / 3 molecules of IL-2 with a K D of 9.53´10 -7 M. Heparin prevented SPMG binding to IL-2 by 72.2%; thus, to a large extent, SPMG and heparin share common binding sites on IL-2. In contrast, other glycosaminoglycans (e.g., chondroitin sulfate and dermatan sulfate) had little effect on SPMG and IL-2 interaction, suggesting the requirement of a defined sequence within the sugar chain for specific recognition of IL-2. Concomitant treatment of IL-2 and SPMG augmented lymphocyte proliferation, compared with IL-2 alone; in contrast, SPMG alone had no proliferative effect. Taken together, our findings demonstrated for the first time that SPMG exerted its immunomodulation by direct activation of T cell function, accompanied by simultaneous modulation of cytokine function, which suggests that SPMG would show great promise for use in anti-AIDS therapy.

T-cell receptor (TCR)/CD3 is involved in sulfated polymannuroguluronate (SPMG)-induced T lymphocyte activation

“…In the present study, the engagement of SPMG with TCR/CD3 complex can be highly proposed to provide a co-stimulatory signal in ConA-stimulated T cells [40]. Importantly, the multivalent binding of SPMG to ConA with relatively high affinity allows for the aggregation and enrichment of ConA in T lymphocytes, which might provide mechanism explanation to support the findings that SPMG significantly promotes ConA-stimulated T-cell proliferative response and lymphokines secretion [9,10].…”

“…In this paper, SPMG binding to TCR/CD3 complex may offer a mechanistic explanation of its cellular immunopotentiating activities both in vivo and in vitro [9,10].…”

“…Our previous investigations have demonstrated that SPMG was able to promote the immunologic functions of T cells via increasing the lymphokines production [10]. To study the immunopotentiating activities of SPMG on T lymphocytes, we first observed the direct effects of SPMG on T-cell proliferative response by MTT assay.…”

“…The fact that coexisting of SPMG and ConA facilitated their binding to T cells might at least partially attribute to the direct interaction between SPMG and ConA. All the data above may provide mechanism explanation to elucidate the observations that SPMG significantly promotes ConA-stimulated T-cell proliferative response and lymphokines secretion [9,10].…”

“…Previous investigations from our group have verified that SPMG exerted strong immunopotentiating actions particularly on T lymphocytes by upregulating CD69 expression, enhancing the production of lymphokines such as interleukin-2 (IL-2) and interferon g (IFN-g), and increasing lymphocytes number and CD4 / CD8 ratio of T cells in peripheral blood. The anti-HIV activities of SPMG may be attributed to its immunopotentiating effects especially on T cells to a great extent [9,10]. SPMG has capability to augment immune response by promoting T cell functions with or without mitogen stimulation, however, the detailed mechanisms remain to be elucidated.…”