Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.
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.
Department of Immunology and Microbial Science, The Scripps Research Institute.
Colleen
C
Doyle-Cooper
Department of Immunology and Microbial Science, The Scripps Research Institute.
Krystalyn E
KE
Hudson
Department of Immunology and Microbial Science, The Scripps Research Institute.
Anthony B
AB
Cooper
Department of Immunology and Microbial Science, The Scripps Research Institute.
Takayuki
T
Ota
Department of Immunology and Microbial Science, The Scripps Research Institute.
Patrick
P
Skog
Department of Chemistry, The Scripps Research Institute.
Phillip E
PE
Dawson
Department of Immunology and Microbial Science, The Scripps Research Institute.
Michael B
MB
Zwick
Department of Immunology and Microbial Science, The Scripps Research Institute.|IAVI Neutralizing Antibody Center.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute.
William R
WR
Schief
Department of Immunology and Microbial Science, The Scripps Research Institute.|IAVI Neutralizing Antibody Center.|Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute.|Ragon Institute of MGH, MIT and Harvard, Charlestown.
Dennis R
DR
Burton
Department of Immunology and Microbial Science, The Scripps Research Institute.
David
D
Nemazee
D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015488:HIV Antigens / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains