Positions

Overview

  • The generation of long-lived, high affinity antibodies is required for protective immunity to most viruses and for protection after vaccination. Thus, it is essential to understand the mechanisms that control the generation of long-lasting protective antibody (Ab) responses. T follicular helper (Tfh) cells, a distinct CD4+ T cell subset that expresses high levels of CXCR5 and localizes in the B cell follicles, play an essential role on promoting long-lived Ab responses. In fact, in the absence of Tfh cells, long-term Ab responses are impaired and protection to pathogens compromised. Therefore, it is essential that we understand how to manipulate Tfh responses in order to improve the efficacy of vaccines. However, despite significant advances in the field, our understanding of how Tfh cells responses are initiated is very limited. Recent studies suggest that Tfh cells are initially primed by dendritic cells (DCs), suggesting that we may be able to develop adjuvants that preferentially activate DCs to promote Tfh cell priming or target vaccine antigens to those DCs that preferentially induce Tfh cells. Unfortunately, we do not know what signals direct the DCs to promote Tfh cell differentiation or which specific subsets of DCs prime Tfh cell responses. Thus, one of the goals of my lab is to determine the cellular interactions, the environmental cues and the molecular mechanisms that control the differential capacity of distinct populations of DCs to regulate Tfh cell responses in different models of infection and autoimmune disease. This knowledge will help us to determine the nature of adjuvants that can be used to boost Tfh cell responses to tumors, pathogens and vaccines. A second project in my lab focuses on the potential clinical benefits of low-dose IL-2 administration to treat autoimmune disease and the mechanisms underlying these effects. Recent studies indicate that low-dose IL-2 treatment suppresses unwanted immune responses in mice and humans, thus evidencing the potential of IL-2 to treat autoimmune disorders (reviewed by us in Immunotherapy. 2014). Increased regulatory T cell activity is one of the potential mechanisms by which low-dose IL-2 immunotherapy induces immunosuppression. However data obtained in my lab indicate that exogenous IL-2 administration prevents aberrant accumulation of Tfh and GC B cell in lupus-prone mice. Our results demonstrate an unexpected immunosuppressive function of IL- 2 that is independent on its role on Treg homeostasis, and provide an alternative mechanism to explain the clinical benefits of IL-2 immunotherapies to treat antibody-mediated autoimmune disorders. These data offer new insights into how polymorphisms in the IL-2 and IL-2R genes can affect self-reactive Tfh and B cell responses and influence the development of autoimmune disease manifestations. We are now exploring the potential therapeutic use of low doses of IL-2 in systemic lupus erythematosus, the potential synergistic effects of combining IL-2 administration with blockade of cytokine pathways that promote Tfh cell development and/or deplete B cells, and how more specifically target IL-2 to Tfh cells.
  • Selected Publications

    Academic Article

    Year Title Altmetric
    2017 Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection.Nature Immunology.  18:1249-1260. 2017
    2017 Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells.Journal of Immunology.  199:2377-2387. 2017
    2017 CCCTC-Binding Factor Translates Interleukin 2- and α-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs.Immunity.  47:251-267.e7. 2017
    2016 The Integrin LFA-1 Controls T Follicular Helper Cell Generation and Maintenance.Immunity.  45:831-846. 2016
    2016 T Follicular Helper Cell Plasticity Shapes Pathogenic T Helper 2 Cell-Mediated Immunity to Inhaled House Dust Mite.Immunity.  44:259-273. 2016
    2016 IL-7 signalling represses Bcl-6 and the TFH gene program.Nature Communications.  7:10285. 2016
    2015 Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production.Scientific Reports.  5:7691. 2015
    2014 The biology of the interleukin-2 (IL-2)-Based immunotherapies in cancer and autoimmune diseaseInternational Journal of Cancer Research and Prevention.  7:213-234. 2014
    2014 Dendritic cells and B cells: unexpected partners in Th2 development.Journal of Immunology.  193:1531-1537. 2014
    2014 Prolonged antigen presentation by immune complex-binding dendritic cells programs the proliferative capacity of memory CD8 T cells.Journal of Experimental Medicine.  211:1637-1655. 2014
    2014 Epitope-specific regulation of memory programming by differential duration of antigen presentation to influenza-specific CD8(+) T cells.Immunity.  41:127-140. 2014
    2014 FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability.Nature Communications.  5:3495. 2014
    2014 Innate IFNγ-producing B cells.Cell Research.  24:135-136. 2014
    2014 Beyond regulatory T cells: the potential role for IL-2 to deplete T-follicular helper cells and treat autoimmune diseases.Immunotherapy.  6:1207-1220. 2014
    2014 Priming of T follicular helper cells by dendritic cells.Immunology and Cell Biology.  92:22-27. 2014
    2013 CD4+ T helper cells use CD154-CD40 interactions to counteract T reg cell-mediated suppression of CD8+ T cell responses to influenza.Journal of Experimental Medicine.  210:1591-1601. 2013
    2012 Unraveling effector functions of B cells during infection: the hidden world beyond antibody production.Infectious Disorders - Drug Targets.  12:213-221. 2012
    2012 Regulation of T(H)2 development by CXCR5+ dendritic cells and lymphotoxin-expressing B cells.Nature Immunology.  13:681-690. 2012
    2012 Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation.Immunity.  36:847-856. 2012
    2011 Memory: the incomplete unhappening of differentiation.Immunity.  35:496-498. 2011
    2010 Erratum: Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8+ T cell responses to influenza (Nature Immunology (2010) 11 (216-224))Nature Immunology.  11:644. 2010
    2010 Temporal changes in dendritic cell subsets, cross-priming and costimulation via CD70 control CD8(+) T cell responses to influenza.Nature Immunology.  11:216-224. 2010
    2007 p21CIP1/WAF1 controls proliferation of activated/memory T cells and affects homeostasis and memory T cell responses.Journal of Immunology.  178:2296-2306. 2007
    2007 Cell cycle inhibitors in T cell tolerance and autoimmunity controlInmunología.  26:184-192. 2007

    Chapter

    Year Title Altmetric
    2014 The biology of the interleukin-2 (IL-2)-based immunotherapies in cancer and autoimmune disease.  31-52. 2014

    Research Overview

  • T cell responses B cell responses Dendritic cell Biology Influenza Autoimmune diseases Vaccines
  • Teaching Activities

    Full Name

  • Andre Ballesteros-Tato
  • Blazerid

  • aballest