Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals.
Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20(hi)/CD27(lo)/CD21(lo)) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20(hi)/CD27(-)/CD21(lo)) when compared with B cells with a classical memory (CD27(+)) or naive (CD27(-)/CD21(hi)) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.
Moir
Susan
S
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. smoir@niaid.nih.gov
Ho
Jason
J
Malaspina
Angela
A
Wang
Wei
W
DiPoto
Angela C
AC
O'Shea
Marie A
MA
Roby
Gregg
G
Kottilil
Shyam
S
Arthos
James
J
Proschan
Michael A
MA
Chun
Tae-Wook
TW
Fauci
Anthony S
AS
D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000821:virology*; D016022:Case-Control Studies; D015483:HIV Antibodies / Q000096:biosynthesis; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D018448:Models, Immunological; D010641:Phenotype; D011961:Receptors, Fc / Q000378:metabolism; D014766:Viremia / Q000276:immunology* / Q000821:virology; D014779:Virus Replication / Q000276:immunology
C423544:FCRL4 protein, human; D015483:HIV Antibodies; D011961:Receptors, Fc