Naive and memory CD4+ T cell subsets can contribute to the generation of human Tfh cells.

CD4+ T follicular helper cells (Tfh) promote B cell maturation and antibody production in secondary lymphoid organs. By using an innovative culture system based on splenocyte stimulation, we studied the dynamics of naive and memory CD4+ T cells during the generation of a Tfh cell response. We found that both naive and memory CD4+ T cells can acquire phenotypic and functional features of Tfh cells. Moreover, we show here that the transition of memory as well as naive CD4+ T cells into the Tfh cell profile is supported by the expression of pro-Tfh genes, including transcription factors known to orchestrate Tfh cell development. Using this culture system, we provide pieces of evidence that HIV infection differentially alters these newly identified pathways of Tfh cell generation. Such diversity in pathways of Tfh cell generation offers a new framework for the understanding of Tfh cell responses in physiological and pathological contexts.

Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice.

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic ß-cells by autoreactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in NOD mice. We investigated the contribution to diabetes of the T-cell receptor (TCR) repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. Interleukin-2 (IL-2) administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2-expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.

Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat.

Under healthy conditions, the blood-brain barrier (BBB) limits the passage of solutes and cells from the blood to the CNS. During neurological diseases, BBB permeability increases dramatically and it has been hypothesized that drug carrier systems such as polymeric nanoparticles could cross the BBB and penetrate into the CNS. PEGylated polyalkylcyanoacrylate nanoparticles (long-circulating carrier) are one such system and have been investigated during experimental allergic encephalomyelitis (EAE). Brain and spinal cord concentrations of [(14)C]-radiolabelled PEGylated polyalkylcyanoacrylate nanoparticles were compared with another blood long-circulating carrier (poloxamine 908-coated polyalkylcyanoacrylate nanoparticles) and with conventional non-long-circulating polyalkylcyanoacrylate nanoparticles. The microscopic localization of fluorescent nanoparticles in the CNS was also investigated in order to further understand the mechanism by which the particles penetrate the BBB. The results demonstrate that the concentration of PEGylated nanoparticles in the CNS, especially in white matter, is greatly increased in comparison to conventional non-PEGylated nanoparticles. In addition, this increase was significantly higher in pathological situations where BBB permeability is augmented and/or macrophages have infiltrated. Passive diffusion and macrophage uptake in inflammatory lesions seems to be the mechanism underlying such particles' brain penetration. Based on their long-circulating properties in blood and on their surface characteristics that allow cell interactions, PEGylated nanoparticles penetrated into CNS to a larger extent than all the other formulations tested. Thus, PEGylated polycyanoacrylate nanoparticles are proposed here as a new brain delivery system for neuroinflammatory diseases.