CD4 T follicular helper cell dynamics during SIV infection
Constantinos Petrovas, … , Elias K. Haddad, Richard A. Koup
Constantinos Petrovas, … , Elias K. Haddad, Richard A. Koup
Published August 27, 2012
Citation Information: J Clin Invest. 2012;122(9):3281-3294. https://doi.org/10.1172/JCI63039.
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Research Article

CD4 T follicular helper cell dynamics during SIV infection

Abstract

CD4 T follicular helper (TFH) cells interact with and stimulate the generation of antigen-specific B cells. TFH cell interaction with B cells correlates with production of SIV-specific immunoglobulins. However, the fate of TFH cells and their participation in SIV-induced antibody production is not well understood. We investigated the phenotype, function, location, and molecular signature of TFH cells in rhesus macaques. Similar to their human counterparts, TFH cells in rhesus macaques represented a heterogeneous population with respect to cytokine function. In a highly differentiated subpopulation of TFH cells, characterized by CD150lo expression, production of Th1 cytokines was compromised while IL-4 production was augmented, and cells exhibited decreased survival, cycling, and trafficking capacity. TFH cells exhibited a distinct gene profile that was markedly altered by SIV infection. TFH cells were infected by SIV; yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH cells was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. Therefore, chronic SIV does not disturb the ability of TFH cells to help B cell maturation and production of SIV-specific immunoglobulins.

Authors

Constantinos Petrovas, Takuya Yamamoto, Michael Y. Gerner, Kristin L. Boswell, Kaska Wloka, Emily C. Smith, David R. Ambrozak, Netanya G. Sandler, Katherina J. Timmer, Xiaoyong Sun, Li Pan, Amanda Poholek, Srinivas S. Rao, Jason M. Brenchley, S. Munir Alam, Georgia D. Tomaras, Mario Roederer, Daniel C. Douek, Robert A. Seder, Ronald N. Germain, Elias K. Haddad, Richard A. Koup

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Figure 6

TFH cell accumulation correlates with increased immune activation and skewed IL-6 signaling.

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TFH cell accumulation correlates with increased immune activation and sk...
(A) Plasma sCD14 levels from noninfected (n = 6), acute (n = 8), and chronic SIV-infected RMs (dark gray: low TFH cells, n = 7; red: high TFH cells, n = 9). (B) Plasma IL-6 levels from noninfected (n = 6) and chronic SIV-infected (n = 12) RMs. (C) IL-6Ra expression on CD4 T cell subsets from noninfected (n = 10), acute (n = 11), and chronic SIV-infected (n = 18) LNs. (D) Linear regression analysis between IL-6Ra and frequency of TFH cells (chronic SIV-infected, n = 18). (E) IL-6–induced pSTAT-1 (3), after subtraction of basal (no stimulation) levels, in CD4 T cells from noninfected (n = 4), acute (n = 4), and chronic SIV-infected (n = 11) LNs. (F) Linear regression analysis between pSTAT-1 (pSTAT-1/pSTAT-3) in PD-1hi CD4 T cells and frequency of TFH cells (chronic SIV-infected RMs, n = 11). (G) Viability and absolute cell numbers (counts after treatment minus initial counts) of sorted LN CD4 T cells (chronic SIV-infected, n = 4) stimulated with anti-CD3 with or without IL-6. (H) Pooled data showing levels of BCL-6 in LN (n = 5) CD4 T cell populations stimulated with anti-CD3 with or without IL-6. Box sizes represent limits of the second and third quartiles, with medians shown as bars. Whiskers define minimum and maximum of data. Each dot represents data for a single sample from an individual animal. Animals are represented once in each plot. Horizontal lines depict mean values. P values were calculated using the (A–C) Mann-Whitney U test or (E) Wilcoxon matched-pairs signed-rank test.