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J Immunol. 2013 Sep 15;191(6):3186-3191. doi: 10.4049/jimmunol.1301285. Epub 2013 Aug 12.

Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.

Author information

1
Department of Immunology and Microbial Science, The Scripps Research Institute.
2
Department of Chemistry, The Scripps Research Institute.
3
IAVI Neutralizing Antibody Center.
4
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute.
5
Ragon Institute of MGH, MIT and Harvard, Charlestown.
#
Contributed equally

Abstract

A major goal of HIV research is to develop vaccines reproducibly eliciting broadly neutralizing Abs (bNAbs); however, this has proved to be challenging. One suggested explanation for this difficulty is that epitopes seen by bNAbs mimic self, leading to immune tolerance. We generated knock-in mice expressing bNAb 4E10, which recognizes the membrane proximal external region of gp41. Unlike b12 knock-in mice, described in the companion article (Ota et al. 2013. J. Immunol. 191: 3179-3185), 4E10HL mice were found to undergo profound negative selection of B cells, indicating that 4E10 is, to a physiologically significant extent, autoreactive. Negative selection occurred by various mechanisms, including receptor editing, clonal deletion, and receptor downregulation. Despite significant deletion, small amounts of IgM and IgG anti-gp41 were found in the sera of 4E10HL mice. On a Rag1⁻/⁻ background, 4E10HL mice had virtually no serum Ig of any kind. These results are consistent with a model in which B cells with 4E10 specificity are counterselected, raising the question of how 4E10 was generated in the patient from whom it was isolated. This represents the second example of a membrane proximal external region-directed bNAb that is apparently autoreactive in a physiological setting. The relative conservation in HIV of the 4E10 epitope might reflect the fact that it is under less intense immunological selection as a result of B cell self-tolerance. The safety and desirability of targeting this epitope by a vaccine is discussed in light of the newly described bNAb 10E8.

PMID:
23940276
PMCID:
PMC3773228
DOI:
10.4049/jimmunol.1301285
[Indexed for MEDLINE]
Free PMC Article

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