Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4 ⁺ T-cell subset specialized for B-cell help outside germinal centers

T follicular helper (Tfh) cells represent a Th subset engaged in the help of B-cell responses in germinal centers (GCs). Tfh cells abundantly express the transcription repressor B-cell lymphoma 6 (Bcl6), a factor that is necessary and sufficient for their development in vivo. Whether Tfh or Tfh-committed cells are involved in the help of B cells outside GCs remains unclear, particularly in humans. In this study, we identified a previously undefined BCL6- expressing CD4 ⁺ T-cell subset in human tonsils. This subset expressed IL-7 receptor and chemokine receptor 5 (CXCR5) and inducible costimulator (ICOS) at low levels (CXCR5 ^loICOS ^lo), and it was found exclusively outside GCs. CXCR5 ^loICOS ^lo CD4 ⁺ T cells secreted larger amounts of IL-21 and IL-10 than CXCR5 ^hiICOS ^hi GC-Tfh cells upon activation, and they induced proliferation and differentiation of naïve B cells into Ig-producing cells more efficiently than GC-Tfh cells. However, this subset lacked the capacity to help GC-B cells because of the induction of apoptosis of GC-B cells through the FAS/FAS-ligand interaction. CXCR5 ^loICOS ^lo CD4 ⁺ T cells expressed equivalent amounts of BCL6 transcript with CXCR5 ^hiICOS ^hi GC-Tfh cells, but they expressed less Bcl6 protein. Collectively, our study indicates that CXCR5 ^loICOS ^lo CD4 ⁺ T cells in human tonsils represent Tfh lineage-committed cells that provide help to naïve and memory B cells outside GCs.