Assembly of a spatial circuit of T-bet–expressing T and B lymphocytes is required for antiviral humoral immunity

Abstract

Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet–expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of TH1 cells at the T-B boundary. The encounter of B and TH1 cells at the T-B boundary enables IFN-γ produced by the latter to induce IgG2c class switching. Within GCs, T-bet+ TFH cells represent a specialized stable sublineage required for GC growth but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet–expressing T and B lymphocytes form a circuit assembled in a spatiotemporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.

Age-associated B cells in viral infection

“…Fate mapping studies have shown that a portion of ABCs are not GC-derived [ 28 ]. B cells outside of the GC express elevated phosphorylated signal transducer and activator of transcription 1 (pSTAT1), upstream of T-bet expression, in B cells [ 17 ], indicating that T-bet is likely up-regulated in B cells prior to GC entry [ 11 ]. It is possible, and has been previously suggested, that ABCs might undergo different differentiation processes and could arise from both within and outside of the GC [ 3 ].…”

“…IgG2a/c (IgG1 in humans) is associated with a Th1 response and is the major antiviral isotype [ 31 , 32 ]. Knocking out ABCs in mice leads to a significant decrease in IgG2a/c titers [ 11 – 13 ], and transfer of virus-specific antibodies into mice deficient in ABCs is able to partially restore control of chronic LCMV [ 12 ].…”

Heterogeneous Tfh cell populations that develop during enteric helminth infection predict the quality of type 2 protective response

“…Although both type 1 and type 2 immune stimuli drive Tfh cell development, the functional capacities of Tfh1 and Tfh2 cells are discrete. In turn, distinct Tfh cell function regulates the outcome of humoral immune responses and the host's immunity [13,18,20]…”

“…Although both type 1 and type 2 immune stimuli drive Tfh cell development, the functional capacities of Tfh1 and Tfh2 cells are discrete. In turn, distinct Tfh cell function regulates the outcome of humoral immune responses and the host's immunity [13,18,20]. The distinct functions of different subpopulations of Tfh cells suggest that they play key nonredundant roles in regulating immunity to a wide range of immune stimuli.…”

Age-associated B cells are long-lasting effectors that restrain reactivation of latent γHV68

“…ABCs are elevated in the spleen and circulation during active viral infections and persist primarily in the spleen during chronic infection or upon infection resolution 7,8 . ABCs display multiple functional capacities including the secretion of antibodies and anti-viral cytokines, and activation of T cells 11,12 . T-bet expression in B cells is required for IgG2a/c class switching 13 and lack of ABCs exacerbates LCMV chronic infection in mice 14 .…”