Follicular helper T cells as cognate regulators of B cell immunity

McHeyzer‐Williams, Louise J.; Pelletier, Nadège; Mark, Linda; Fazilleau, Nicolas; McHeyzer‐Williams, Michael G.

doi:10.1016/j.coi.2009.05.010

Cited by 170 publications

(137 citation statements)

References 57 publications

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…Within the same series of studies, IL-21R-deficient mice were also reported to have activation of a normal memory B cell response; however, quantitative analysis to support this assertion was not provided (17 (12,23). Alternatively, IL-21 may affect the differentiation program of B cells during the primary response or the quality of T cell help available, both of which could indirectly impact the characteristics of memory B cell response (41,42). Future studies will aim to determine the mechanism by which IL-21 augments the memory B cell response.…”

Section: Discussionmentioning

confidence: 99%

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Rankin

MacLeod

Keegan

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Development of long-term humoral immunity, characterized by the formation of long-lived plasma cells (PCs) in the bone marrow and memory B cells, is a critical component of protective immunity to pathogens, and as such it is the major goal of vaccination. However, the mechanisms involved in the generation of long-term humoral immunity remain poorly understood. In this study, we used IL-21R–deficient (IL-21R.KO) mice to examine the role of the IL-21 pathway in the development of the B cell memory response. Primary IgG serum Ab responses to the T cell-dependent Ag 4-hydroxy-3-nitrophenylacetyl (NP) hapten conjugated to chicken γ globulin were delayed in IL-21R.KO mice, but reached normal titers within 3 to 4 wk of immunization. IL-21R.KO mice formed germinal centers and generated normal numbers of PCs in their bone marrow. Additionally, memory B cell formation was similar in wild-type and IL-21R.KO mice. However, NP-specific memory B cells and PCs failed to expand following secondary immunization of IL-21R.KO mice, and consequently, secondary IgG Ab responses to NP hapten conjugated to chicken γ globulin were significantly impaired. These results identify the IL-21 pathway as a critical component of the memory B cell response.

show abstract

Section: Discussionmentioning

confidence: 99%

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Rankin

MacLeod

Keegan

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Another possibility for uncontrolled B-cell activation in MyD88 À/À mice after RASV infection is failure in the feedback regulation of Tfh-cell generation and function by plasma cells. Recently, plasma cells were reported to regulate Tfh cells in an antigen-specific manner and mice deficient in plasma cells showed lack of negative feedback regulation for Tfh-cell activity [41,42]. Collectively, systemic hyper-IgG Ab response to persistent bacterial exposure might be initiated as a danger signal to provoke immune responses but fail to control the infection due to the lack of proper defense by the MyD88 molecule.…”

Section: Discussionmentioning

confidence: 99%

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

Yang

et al. 2011

Eur J Immunol

View full text Add to dashboard Cite

The role of TLR signaling in linking the innate and adaptive immune systems has been a controversial issue that remains to be solved. Here, we determined whether MyD88-dependent TLR signals are required for the generation of B-cell responses during chronic Salmonella infection. Oral administration of recombinant attenuated Salmonella enterica serovar Typhimurium vaccine (RASV) strain in MyD88 À/À mice resulted in chronic infection. Infection was accompanied by enlarged germinal centers and hypergammaglobulinemia with anti-double-stranded DNA (dsDNA)-specific Ab in sera, and the deposition of immune complexes in the kidneys, suggesting onset of autoimmunity. CD4 1 T cells expressing PD-1, CXCR5, ICOS, and IL-21 were dramatically increased in chronically infected mice, indicating the expansion of follicular helper T (Tfh)-like cells. Of note, the depletion of CD4 1 T cells completely blocked the generation of polyclonal IgG Ab in sera after oral RASV challenge. Inflammatory myeloid cells expressing CD11b and Gr-1 accumulated in high numbers in the spleen of MyD88 À/À mice. Interestingly, the blockade of PD-1 or ICOS significantly reduced the hypergammaglobulinemia and dsDNA-specific autoantibody production. Overall, these results suggest that Tfh-like cells in chronic bacterial infection trigger autoimmune hypergammaglobulinemia in a PD-1-and ICOSdependent manner.

show abstract

“…The GC reaction is constrained by B-cell-extrinsic factors, including the size of the T FH population and Ag availability (16,17). B cells bearing high-affinity BCR out-compete lower affinity clones for access to T cell-mediated survival signals (18).…”

Section: Np-specific H2-o −/− B Cells Preferentially Populate the Gc mentioning

confidence: 99%

“…Therefore, rather than further study T-cell responses to the presentation of individual peptides, we measured the ability of GC B cells to obtain T-cell help from the pool of endogenous polyclonal CD4 + T cells. This sensitive and physiological approach allows the detection of overall differences in the efficiency of presentation of a polyvalent Ag by WT versus H2-O −/− B cells.The GC reaction is constrained by B-cell-extrinsic factors, including the size of the T FH population and Ag availability (16,17). B cells bearing high-affinity BCR out-compete lower affinity clones for access to T cell-mediated survival signals (18).…”

mentioning

confidence: 99%

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

Draghi¹,

Denzin

2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Upon antigen (Ag) encounter, B cells require T-cell help to enter the germinal center (GC). They obtain this help by presenting Agderived peptides on MHC class II (MHCII) for recognition by the T-cell receptor (TCR) of CD4 + T cells. Peptides are loaded onto MHCII in endosomal compartments in a process catalyzed by the MHCII-like protein H2-M (HLA-DM in humans). This process is modulated by another MHCII-like protein, H2-O (HLA-DO in humans). H2-O is a biochemical inhibitor of peptide loading onto MHCII; however, on the cellular level, it has been shown to have varying effects on Ag presentation. Thus, the function of H2-O in the adaptive immune response remains unclear. Here, we examine the effect of H2-O expression on the ability of Ag-specific B cells to enter the GC. We show that when Ag specific WT and H2-O −/− B cells are placed in direct competition, H2-O −/− B cells preferentially populate the GC. This advantage is confined to Ag-specific B cells and is due to their superior ability to obtain Ag-specific T-cell help when T-cell help is limiting. Overall, our work shows that H2-O expression reduces the ability of B cells to gain T-cell help and participate in the GC reaction.antigen processing | antigen presentation | H2-M | follicular helper T cells | HLA-DOA ntigen (Ag) processing and presentation on MHCII is central to T cell-dependent Ab-mediated immunity. During an immune response, Ag-specific naïve B cells recognize and internalize Ag via the B-cell receptor (BCR). The Ag is subsequently transported to late endosomes and lysosomes, where it is degraded into peptides, some of which are loaded onto MHC class II (MHCII) (1). These MHCII-peptide complexes are then displayed on the cell surface for recognition by cognate CD4 + T cells. This recognition event allows B cells to obtain T-cell help from a rare population of T cells known as CD4 + follicular helper T cells (T FH ). The interaction between the Ag-specific B cells and T FH cells is essential for B-cell entry into the germinal center (GC) (2).Peptide loading of MHCII is catalyzed by the nonclassical MHCII-like protein H2-M (HLA-DM in humans) (3-5). H2-M, which localizes to endosomes (6), promotes the removal of class IIassociated invariant chain peptides (CLIP) from the peptidebinding groove of MHCII. H2-M also stabilizes empty MHCII molecules and edits the final MHCII-bound peptide repertoire that is displayed at the cell surface to ensure that only long-lived MHCII-peptide complexes are presented (7). Another nonclassical MHCII-like protein, H2-O (HLA-DO in humans), also localizes to endosomes in B cells (8). H2-O forms a complex with H2-M and has been shown to inhibit or modulate the ability of H2-M to catalyze and edit MHCII peptide exchange (9-12). Surprisingly, H2-O-deficient mice exhibit only minor abnormalities in Ag presentation (11, 13).Ag presentation is important for many aspects of immunity, including initiating the GC response. Admission of B cells into the GC is a competitive process that is dependent upon help from Agspecific T F...

show abstract

Follicular helper T cells as cognate regulators of B cell immunity

Cited by 170 publications

References 57 publications

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

IL-21 Receptor Is Critical for the Development of Memory B Cell Responses

Expansion of Tfh‐like cells during chronic Salmonella exposure mediates the generation of autoimmune hypergammaglobulinemia in MyD88‐deficient mice

H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers

Contact Info

Product

Resources

About