A T cell-dependent mechanism for the induction of human mucosal homing immunoglobulin A-secreting plasmablasts.
Mucosal immunoglobulin A (IgA) secreted by local plasma cells (PCs) is a critical component of mucosal immunity. Although IgA class switching can occur at mucosal sites, high-affinity PCs are optimally generated in germinal centers (GCs) in a T cell-dependent fashion. However, how CD4(+) helper T cells induce mucosal-homing IgA-PCs remains unclear. Here, we show that transforming growth factor beta1 (TGFbeta1) and interleukin 21 (IL-21), produced by follicular helper T cells (Tfh), synergized to generate abundant IgA-plasmablasts (PBs). In the presence of IL-21, TGFbeta1 promoted naive B cell proliferation and differentiation and overrode IL-21-induced IgG class switching in favor of IgA. Furthermore, TGFbeta1 and IL-21 downregulated CXCR5 while upregulating CCR10 on plasmablasts, enabling their exit from GCs and migration toward local mucosa. This was supported by the presence of CCR10(+)IgA(+)PBs in tonsil GCs. These findings show that Tfh contribute to mucosal IgA. Thus, mucosal vaccines should aim to induce robust Tfh responses.
Dullaers
Melissa
M
Baylor Institute for Immunology Research, Baylor Research Institute and INSERM 899, Dallas, TX 75204, USA.
Li
Dapeng
D
Xue
Yaming
Y
Ni
Ling
L
Gayet
Ingrid
I
Morita
Rimpei
R
Ueno
Hideki
H
Palucka
Karolina Anna
KA
Banchereau
Jacques
J
Oh
Sangkon
S
D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte; D002648:Child; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007070:Immunoglobulin A / Q000145:classification / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000502:physiology; D009092:Mucous Membrane / Q000276:immunology*; D010950:Plasma Cells / Q000276:immunology*; D016133:Polymerase Chain Reaction; D054447:Receptors, CCR10 / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012015:Reference Standards; D013601:T-Lymphocytes / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D015854:Up-Regulation; D000098546:Interleukin-21
C515706:CCR10 protein, human; C095085:CXCR5 protein, human; D007070:Immunoglobulin A; D007376:Interleukin-2; D007378:Interleukins; D054447:Receptors, CCR10; D054380:Receptors, CXCR5; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D000098546:Interleukin-21