Loss of circulating CD4 T cells with B cell helper function during chronic HIV infection.
The interaction between follicular T helper cells (TFH) and B cells in the lymph nodes and spleen has a major impact on the development of antigen-specific B cell responses during infection or vaccination. Recent studies described a functional equivalent of these cells among circulating CD4 T cells, referred to as peripheral TFH cells. Here, we characterize the phenotype and in vitro B cell helper activity of peripheral TFH populations, as well as the effect of HIV infection on these populations. In co-culture experiments we confirmed CXCR5+ cells from HIV-uninfected donors provide help to B cells and more specifically, we identified a CCR7(high)CXCR5(high)CCR6(high)PD-1(high) CD4 T cell population that secretes IL-21 and enhances isotype-switched immunoglobulin production. This population is significantly decreased in treatment-naïve, HIV-infected individuals and can be recovered after anti-retroviral therapy. We found impaired immunoglobulin production in co-cultures from HIV-infected individuals and found no correlation between the frequency of peripheral TFH cells and memory B cells, or with neutralization activity in untreated HIV infection in our cohort. Furthermore, we found that within the peripheral TFH population, the expression level of TFH-associated genes more closely resembles a memory, non-TFH population, as opposed to a TFH population. Overall, our data identify a heterogeneous population of circulating CD4 T cells that provides in vitro help to B cells, and challenges the origin of these cells as memory TFH cells.
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Kristin L
KL
Boswell
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America ; United States Military HIV Research Program, Rockville, Maryland, United States of America.
Robert
R
Paris
Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Eli
E
Boritz
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
David
D
Ambrozak
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Takuya
T
Yamamoto
Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Sam
S
Darko
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Kaska
K
Wloka
Immunology Core Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Adam
A
Wheatley
Immunology Core Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Sandeep
S
Narpala
Immunology Core Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Adrian
A
McDermott
ImmunoTechnology Section, Vaccine Research Center, National Institutes of Health, Bethesda, Maryland, United States of America.
Mario
M
Roederer
Division of Infectious Diseases, Antiviral Research Center, University of California San Diego, San Diego, California, United States of America.
Richard
R
Haubrich
HIV-Specific Immunity Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland, United States of America.
Mark
M
Connors
United States Military HIV Research Program, Rockville, Maryland, United States of America.
Julie
J
Ake
Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Daniel C
DC
Douek
United States Military HIV Research Program, Rockville, Maryland, United States of America.
Jerome
J
Kim
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Constantinos
C
Petrovas
Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, United States of America.
Richard A
RA
Koup
D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D006801:Humans; D007156:Immunologic Memory; D008297:Male; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
D057134:Antibodies, Neutralizing; D000943:Antigens, Differentiation; D015483:HIV Antibodies