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Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5.

Publication ,  Journal Article
Finney, J; Yang, G; Kuraoka, M; Song, S; Nojima, T; Verkoczy, L; Kitamura, D; Haynes, BF; Kelsoe, G
Published in: J Immunol
December 15, 2019

2F5 is an HIV-1 broadly neutralizing Ab that also binds the autoantigens kynureninase (KYNU) and anionic lipids. Generation of 2F5-like Abs is proscribed by immune tolerance, but it is unclear which autospecificity is responsible. We sampled the BCR repertoire of 2F5 knock-in mice before and after the first and second tolerance checkpoints. Nearly all small pre-B (precheckpoint) and 35-70% of anergic peripheral B cells (postcheckpoint) expressed the 2F5 BCR and maintained KYNU, lipid, and HIV-1 gp41 reactivity. In contrast, all postcheckpoint mature follicular (MF) B cells had undergone L chain editing that purged KYNU and gp41 binding but left lipid reactivity largely intact. We conclude that specificity for KYNU is the primary driver of tolerization of 2F5-expressing B cells. The MF and anergic B cell populations favored distinct collections of editor L chains; surprisingly, however, MF and anergic B cells also frequently expressed identical BCRs. These results imply that BCR autoreactivity is the primary determinant of whether a developing B cell enters the MF or anergic compartments, with a secondary role for stochastic factors that slightly mix the two pools. Our study provides mechanistic insights into how immunological tolerance impairs humoral responses to HIV-1 and supports activation of anergic B cells as a potential method for HIV-1 vaccination.

Duke Scholars

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Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

December 15, 2019

Volume

203

Issue

12

Start / End Page

3268 / 3281

Location

United States

Related Subject Headings

  • Receptors, Antigen, B-Cell
  • Mice, Inbred C57BL
  • Mice
  • Lymphocyte Activation
  • Immunology
  • Immune Tolerance
  • Hydrolases
  • Humans
  • HIV-1
  • HIV Antibodies
 

Citation

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MLA
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Finney, J., Yang, G., Kuraoka, M., Song, S., Nojima, T., Verkoczy, L., … Kelsoe, G. (2019). Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5. J Immunol, 203(12), 3268–3281. https://doi.org/10.4049/jimmunol.1900069
Finney, Joel, Guang Yang, Masayuki Kuraoka, Shengli Song, Takuya Nojima, Laurent Verkoczy, Daisuke Kitamura, Barton F. Haynes, and Garnett Kelsoe. “Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5.J Immunol 203, no. 12 (December 15, 2019): 3268–81. https://doi.org/10.4049/jimmunol.1900069.
Finney J, Yang G, Kuraoka M, Song S, Nojima T, Verkoczy L, et al. Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5. J Immunol. 2019 Dec 15;203(12):3268–81.
Finney, Joel, et al. “Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5.J Immunol, vol. 203, no. 12, Dec. 2019, pp. 3268–81. Pubmed, doi:10.4049/jimmunol.1900069.
Finney J, Yang G, Kuraoka M, Song S, Nojima T, Verkoczy L, Kitamura D, Haynes BF, Kelsoe G. Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5. J Immunol. 2019 Dec 15;203(12):3268–3281.

Published In

J Immunol

DOI

EISSN

1550-6606

Publication Date

December 15, 2019

Volume

203

Issue

12

Start / End Page

3268 / 3281

Location

United States

Related Subject Headings

  • Receptors, Antigen, B-Cell
  • Mice, Inbred C57BL
  • Mice
  • Lymphocyte Activation
  • Immunology
  • Immune Tolerance
  • Hydrolases
  • Humans
  • HIV-1
  • HIV Antibodies