HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors.
Switching from IgM to IgG and IgA is essential for antiviral immunity and requires engagement of CD40 on B cells by CD40L on CD4(+) T cells. HIV-1 is thought to impair CD40-dependent production of protective IgG and IgA by inducing progressive loss of CD4(+) T cells. Paradoxically, this humoral immunodeficiency is associated with B cell hyperactivation and increased production of nonprotective IgG and IgA that are either nonspecific or specific for HIV-1 envelope glycoproteins, including gp120. Nonspecific and gp120-specific IgG and IgA are sensitive to antiretroviral therapy and remain sustained in infected individuals with very few CD4(+) T cells. One interpretation is that some HIV-1 Ags elicit IgG and IgA class switch DNA recombination (CSR) in a CD40-independent fashion. We show that a subset of B cells binds gp120 through mannose C-type lectin receptors (MCLRs). In the presence of gp120, MCLR-expressing B cells up-regulate the CSR-inducing enzyme, activation-induced cytidine deaminase, and undergo CSR from IgM to IgG and IgA. CSR is further enhanced by IL-4 or IL-10, whereas Ab secretion requires a B cell-activating factor of the TNF family. This CD40L-related molecule is produced by monocytes upon CD4, CCR5, and CXCR4 engagement by gp120 and cooperates with IL-4 and IL-10 to up-regulate MCLRs on B cells. Thus, gp120 may elicit polyclonal IgG and IgA responses by linking the innate and adaptive immune systems through the B cell-activating factor of the TNF family. Chronic activation of B cells through this CD40-independent pathway could impair protective T cell-dependent Ab responses by inducing immune exhaustion.
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Bing
B
He
Xugang
X
Qiao
Per J
PJ
Klasse
April
A
Chiu
Amy
A
Chadburn
Daniel M
DM
Knowles
John P
JP
Moore
Andrea
A
Cerutti
D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics*; D007136:Immunoglobulins / Q000096:biosynthesis / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008358:Mannose / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
D053264:B-Cell Activating Factor; D015704:CD4 Antigens; D019013:CD40 Antigens; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D007136:Immunoglobulins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D011947:Receptors, Antigen, B-Cell; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; D008358:Mannose