Journal
SCIENCE IMMUNOLOGY
Volume 3, Issue 22, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aan8884
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Funding
- Medical Research Grant from W.W. Smith Charitable Trust Foundation
- Penn Center for AIDS Research Pilot and Feasibility grant [P30-AI045008]
- Veterans Affairs Merit Award [IMMA-020-15F]
- NIH National Institute of Allergy and Infectious Diseases [R01AI134879]
- NIH [R00AG040149, S10OD020072]
- Welch Foundation [F1785]
- Thrust 2000-George Sawyer Endowed Graduate Fellowship in Engineering
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Follicular helper CD4(+)T cells (T-FH) play an integral role in promoting B cell differentiation and affinity maturation. Whereas T-FH cell frequencies are increased in lymph nodes (LNs) from individuals infected with HIV, humoral immunity remains impaired during chronic HIV infection. Whether HIV inhibits T-FH responses in LNs remains unclear. Advances in this area have been limited by the difficulty of accessing human lymphoid tissues. Here, we combined high-dimensional mass cytometry with T cell receptor repertoire sequencing to interrogate the composition of T-FH cells in primary human LNs. We found evidence for intact antigen-driven clonal expansion of T-FH cells and selective utilization of specific complementarity-determining region 3 (CDR3) motifs during chronic HIV infection, but the resulting T-FH cells acquired an activation-related T-FH cell signature characterized by interleukin-21 (IL-21) dominance. These IL-21(+) T-FH cells contained an oligoclonal HIV-reactive population that preferentially accumulated in patients with severe HIV infection and was associated with aberrant B cell distribution in the same LN. These data indicate that T-FH cells remain capable of responding to HIV antigens during chronic HIV infection but become functionally skewed and oligoclonally restricted under persistent antigen stimulation.
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