Signals that drive T-bet expression in B cells

Abstract

Transcription factors regulate various developmental and functional aspects of B cells. T-bet is a recently appreciated transcription factor associated with “Age-associated B cells” or ABCs, the development of autoimmunity, and viral infections. T-bet expression is favored by nucleic acid-containing antigens and immune complexes and is regulated by interplay between various cytokines, notably, the TFH cytokines IL-21, IL-4 and IFNγ. Adaptive signals by themselves cannot upregulate T-bet; however, they have a synergistic effect on induction of T-bet by innate receptors. The functional role of T-bet + B cells is unclear, although it is known that T-bet promotes class switching to IgG2a/c. It is likely T-bet serves dichotomous roles in B cells, promoting pathogenic autoreactive antibodies on one hand but mediating microbial immunity on the other, making it a target of interest in both therapeutic and prophylactic settings.

Innate-like B cell subsets during immune responses: Beyond antibody production

“…Contrasting with FO and MZ B cells, ABCs do not depend on BAFF for survival; however, they express BAFFR/BR3 and TACI receptors for this cytokine . Furthermore, and unlike these 2 mentioned lineages, they are not the product of B lymphopoiesis in the aged microenvironment, nor do they seem to be self‐renewing . Then, it seems that the origin of these lymphocytes can be traced to exhaustive‐expanded FO B cells …”

“…100 Furthermore, and unlike these 2 mentioned lineages, they are not the product of B lymphopoiesis in the aged microenvironment, nor do they seem to be self-renewing. 103,104 Then, it seems that the origin of these lymphocytes can be traced to exhaustive-expanded FO B cells. 105 Regarding the necessary elements that are involved in ABCs generation besides T-bet, the initial characterization of this B cell subset demonstrated that TLR7, TLR9, and MyD88, but not IFN-R, are required for the accumulation of these cells.…”

“…100,106,108,109 ABCs innate-like nature is exemplified by poor responsiveness to BCR and CD40 ligation, despite they possess IgM surface-levels comparable to those seen in conventional FO B cells; instead, they efficiently respond to TLR7 and TLR9 ligation, both innate receptors that synergize with BCR signaling to induce stronger proliferation outcomes. 100 ABCs mainly secrete Igs after TLRs (but not BCR only) stimulation 103,110 ; thus being able to rapidly differentiate into Ab-secreting plasma cells preferentially switched to IgG2a or IgG2c classes. 101,105 They also have been described as robust producers of cytokines such as IL-10 and IFN-.…”

T‐bet+ memory B cells: Generation, function, and fate

“…Within these, further phenotypic and functional categories exist; for example, phenotypically defined T cell subsets differ in anatomic location, cytokine profiles, and the key transcriptional regulators that control these features. [21][22][23][24][25][26] These T-bet + B cells have been identified in both mice and humans in a variety of contexts, including aging, [27][28][29] autoimmunity, 28,[30][31][32][33][34] and infection. Thus, Bmem with distinct phenotypic and functional abilities have been described by several groups, [11][12][13][14][15][16] and PC pools with profoundly different turnover rates are now appreciated.…”

“…Similarly, different mature pre-immune lymphocyte subsets such as transitional (TR), follicular (FO), marginal zone (MZ), and B1 B cells have characteristic anatomic distributions and play distinct roles in primary immune responses. [21][22][23][24][25][26] These T-bet + B cells have been identified in both mice and humans in a variety of contexts, including aging, [27][28][29] autoimmunity, 28,30-34 and infection. Within these, further phenotypic and functional categories exist; for example, phenotypically defined T cell subsets differ in anatomic location, cytokine profiles, and the key transcriptional regulators that control these features.…”