Several mechanisms to explain defects in T cell regeneration exist but Mymetics is highly interested in one particular detect or dysfunction of T cell regeneration, regarding the relevance of the IL-2 cytokine/IL-2 receptor hormone system.

Interleukine-2 belongs to the big cytokine family. These are proteins secreted from cells in response to an infection or tissue damage. Acting either singly or with each other, they form a large network of intracellular communication that governs host defenses against pathogens and tumors. Each cytokine binds to a distinct cell surface receptor, leading to the activation of specific gene products in the target cells, which mediate the biological responses. Interleukin-2 (IL-2), which was first discovered in the culture supernatant of activated T cells, is mainly produced by dividing (in cell cycle) CD4+ T cells that have received an immunostimulatory signals such as antigens, mitogenic lectins, or T-cell specific monoclonal antibodies. Interleukine-2 is a major regulatory lymphokine that causes growth and differentiation of resting and activated T cells, B cells, natural killer cells, and monocytic lineage cells.

The IL-2 mediates its effects through interaction with its cell surface receptors, the IL-2 receptor (IL-2R). It is known that T-cell cycle progression depends on IL-2 receptor (IL-2R) engagement by interleukine-2 (IL-2). The IL-2 receptor may potentially be constituted by three different glycoproteins: the α chain (IL-2R α ), the β chain (IL-2R β ), and the g chain (IL-2R γ ). Interleukin 2 is a major regulatory lymphokine that causes growth and differentiation of resting and activated T cells, B cells, natural killer cells, and monocytic lineage cells. Depending of the association of those subunits, three classes of IL-2 receptor have been identified in vivo. The high-affinity IL-2R (Kd 10 -11 M) containing three distinct subunits: IL-2R α, IL-2R β and IL-2R γ ; intermediate-affinity IL-2R (Kd 10 -9 M) contains two subunits: IL-2R β and IL-2R γ . Finally, the low-affinity IL-2R (Kd 10 -8 M) consisting of only one subunit: IL-2 α . Generally, the IL-2R β and IL-2R γ are constitutively expressed on T cells, while the soluble α chain is expressed only when T cells are activated by an antigen or mitogen. Moreover, the membrane expressed IL-2R α can be released from the cell surface of T and B cells as a soluble IL-2R a following protease digestion. Another important aspect concerns the fact that the IL-2R γ chain is also shared by several other cytokines. Indeed, the gamma chain serves as a subunit for five important cytokines: IL-4, IL-7, IL-9, IL-15 et IL-21. Therefore, Mymetics has postulated that the presence of membrane bound gp41 and/or free gp41 proteins in blood or lymph nodes might behave like an antagonist of the IL-2, once bound to the IL-2R γ . Consequently, gp41 binding on several cell types bearing the IL-2R γ may likely promote anergy or apoptosis.

IL-2 can also reverse in vitro T cell clonal anergy (T cells that are in sleeping mode, so not active and useless) and rescue T lymphocytes from apoptosis (death). The regulation of Bcl-2 seems to be at least in part under the control of IL-2 lymphokine. Absence of IL-2, low IL-2 concentration or defective IL-2 receptor could all potentially contribute to an inadequate Bcl-2 expression, affecting lymphocyte survival of HIV-infected subjects. All these observations suggest that IL-2 delivers various signals to a wide range of cell type via interaction with its receptor. Because of the central role of IL-2 in immune regulation, any dysfunction in IL-2 production and in IL-2R subunits expression may lead to profound immunodeficiency or affect the proportion of T cells entering into the cell cycle.