Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination

Abstract

Adenosine A2a receptor (A2aR) signaling acts as a barrier to autoimmunity by promoting anergy, inducing regulatory T cells (Tregs), and inhibiting effector T cells. However, in vivo effects of A2aR signaling on polyclonal CD4 T cells during a primary response to foreign antigen has yet to be determined. To address this problem, we immunized mice with peptide antigen 2W1S coupled to PE in CFA and treated with the selective A2aR agonist CGS-21680 (CGS). 2W1S:I-Ab-specific tetramer-binding CD4 T cells did not become anergic or differentiate into Foxp3+ Tregs. Additionally, CGS treatment did not inhibit Th1 or Th17 differentiation. However, CGS did abrogate germinal center (GC) T follicular helper (Tfh) cells, and blunted PE-specific GC B cell responses. The use of A2aR-deficientCD4 T cells established that this CGS effect was T cell-intrinsic. Therefore, this study has identified a unique role for A2aRs in regulating CD4 T cell differentiation during vaccination.

Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells

“…Purified naive KRN T cells were then adoptively transferred (~10,000 cells per recipient) via tail vein injection into either wild‐type or Tcra −/− F1 host mice to initiate the recognition of the GPI/I‐A g7 self antigen (Figures A–C). Beginning 1 day after adoptive transfer, host mice were given intraperitoneal injections of the selective A2aR agonist CGS twice daily, at a dose of 2.5 mg/kg (Tocris), or with vehicle alone (phosphate buffered saline [PBS]), as previously described .…”

“…Investigations in our laboratory and others have recently determined that A2aR signaling during the primary response to a foreign antigen in strong adjuvant has the ability to divert CD4 T cell differentiation away from the follicular helper T (Tfh) and germinal center (GC)–Tfh cell lineages, and consequently could reduce help for the differentiation of antigen‐specific GC B cells and isotype class–switched plasmablasts . In RA, autoreactive B cells are thought to be induced by Tfh cells to undergo clonal expansion, isotype class–switch recombination, and somatic hypermutation within the GCs, and this ultimately leads to the differentiation of anti–citrullinated protein antibody–secreting plasma cells .…”

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…98 Using adoptive cell transfer models, we observed that transferred OVA-specific TCR-transgenic CD4 + T cells from Rag −/− mice (devoid of Foxp3 + Treg cells) into Rag-sufficient mice did not give rise to Tfr cells following OVA-IFA immunization, while OVA-specific TCR-transgenic cells from Rag +/+ mice (with thymic Foxp3 + Treg cells) gave rise to Tfr cells. 109 CTLA-4 has a widely known function in maintaining immune homeostasis and in mediating Treg cell function. Indeed, while OVA-specific TCR-transgenic CD4 + T cells were overrepresented within Tfh cells of OVA-immunized mice (compared to mice immunized with a control protein), OVA-specific Tfr cells were found in the same proportion in the two immunizing conditions.…”

“…60 [104][105][106][107][108] Curiously, a recent report found that adenosine A2a receptor agonists can limit GC and Tfh cell responses following immunization, suggesting adenosine may indeed be a key mediator of Tfr-cell effector functions in humoral responses. 109 CTLA-4 has a widely known function in maintaining immune homeostasis and in mediating Treg cell function. 53,[110][111][112] Indeed, mice selectively lacking CTLA-4 expression on Treg cells succumbed to spontaneous lymphoproliferation with fatal T-cell-dependent autoimmune disease.…”

Alum adjuvant is more effective than MF59 at prompting early germinal center formation in response to peptide-protein conjugates and enhancing efficacy of a vaccine against opioid use disorders

“…11 For antigen-based magnetic enrichment, 2W1S peptide was conjugated either to APC or PE (2Wp:MHCII tetramers) as described. 30,35,36 Immunization Mice were immunized s.c. with 75 μg of either OXY-KLH or unconjugated KLH as control. In studies focusing on analysis of 2W1S-specific T cell populations, mice were immunized s. c. with 25 μg of 2W1S SA-PE.…”