Parallel processing in immune networks

In this work we adopt a statistical mechanics approach to investigate basic, systemic features exhibited by adaptive immune systems. The lymphocyte network made by B-cells and T-cells is modeled by a bipartite spin-glass, where, following biological prescriptions, links connecting B-cells and T-cells are sparse. Interestingly, the dilution performed on links is shown to make the system able to orchestrate parallel strategies to fight several pathogens at the same time; this multitasking capability constitutes a remarkable, key property of immune systems as multiple antigens are always present within the host. We also define the stochastic process ruling the temporal evolution of lymphocyte activity, and show its relaxation toward an equilibrium measure allowing statistical mechanics investigations. Analytical results are compared with Monte Carlo simulations and signal-to-noise outcomes showing overall excellent agreement. Finally, within our model, a rationale for the experimentally well-evidenced correlation between lymphocytosis and autoimmunity is achieved; this sheds further light on the systemic features exhibited by immune networks.Comment: 21 pages, 9 figures; to appear in Phys. Rev.

P16-45. High avidity CD4+ T cell response directed to an immunodominant Gag epitope in HIV controllers: an ANRS EP36 study

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The First α Helix of Interleukin (Il)-2 Folds as a Homotetramer, Acts as an Agonist of the IL-2 Receptor β Chain, and Induces Lymphokine-Activated Killer Cells

Interleukin (IL)-2 interacts with two types of functional receptors (IL-2Rαβγ and IL-2Rβγ) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. For the first time, we show that a chemically synthesized fragment of the IL-2 sequence can fold into a molecule mimicking the quaternary structure of a hemopoietin. Indeed, peptide p1–30 (containing amino acids 1–30, covering the entire α helix A of IL-2) spontaneously folds into an α-helical homotetramer and stimulates the growth of T cell lines expressing human IL-2Rβ, whereas shorter versions of the peptide lack helical structure and are inactive. We also demonstrate that this neocytokine interacts with a previously undescribed dimeric form of IL-2Rβ. In agreement with its binding to IL-2Rβ, p1–30 activates Shc and p56lck but unlike IL-2, fails to activate Janus kinase (Jak)1, Jak3, and signal transducer and activator of transcription 5 (STAT5). Unexpectedly, we also show that p1–30 activates Tyk2, thus suggesting that IL-2Rβ may bind to different Jaks depending on its oligomerization. At the cellular level, p1–30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8low lymphocytes and natural killer cells, which constitutively express IL-2Rβ. A significant interferon γ production is also detected after p1–30 stimulation. A mutant form of p1–30 (Asp20→Lys), which is likely unable to induce vascular leak syndrome, remains capable of generating LAK cells, like the original p1–30 peptide. Altogether, our data suggest that p1–30 has therapeutic potential

Altered Responses to Homeostatic Cytokines in Patients with Idiopathic CD4 Lymphocytopenia

Idiopathic CD4 lymphocytopenia (ICL) is a rare immune deficiency characterized by a protracted CD4+ T cell loss of unknown etiology and by the occurrence of opportunistic infections similar to those seen in AIDS. We investigated whether a defect in responses to cytokines that control CD4+ T cell homeostasis could play a role in ICL. Immunophenotype and signaling responses to interleukin-7 (IL-7), IL-2, and thymic stromal lymphopoietin (TSLP) were analyzed by flow cytometry in CD4+ T cells from 15 ICL patients and 15 healthy blood donors. The induction of phospho-STAT5 after IL-7 stimulation was decreased in memory CD4+ T cells of some ICL patients, which correlated with a decreased expression of the IL-7R\uce\ub1 receptor chain (R = 0.74, p<0.005) and with lower CD4+ T cell counts (R = 0.69, p<0.005). IL-2 responses were also impaired, both in the Treg and conventional memory subsets. Decreased IL-2 responses correlated with decreased IL-7 responses (R = 0.75, p<0.005), pointing to combined defects that may significantly perturb CD4+ T cell homeostasis in a subset of ICL patients. Unexpectedly, responses to the IL-7-related cytokine TSLP were increased in ICL patients, while they remained barely detectable in healthy controls. TSLP responses correlated inversely with IL-7 responses (R = -0.41; p<0.05), suggesting a cross-regulation between the two cytokine systems. In conclusion, IL-7 and IL-2 signaling are impaired in ICL, which may account for the loss of CD4+ T cell homeostasis. Increased TSLP responses point to a compensatory homeostatic mechanism that may mitigate defects in \uce\ub3c cytokine responses. \uc2\ua9 2013 Bugault et al

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd