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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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 5

TFH cells are characterized by low cell cycling capacity and increased sensitivity to in vitro cell death.

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TFH cells are characterized by low cell cycling capacity and increased s...
(A) The schedule of the in vivo administration of BrdU and collection of LN tissues from chronic SIV-infected RMs (n = 3) as well as the percentage of Ki67hiBrdUhi cells in naive, CM, and EM CD4 T cell populations are shown. The frequency (%) of Ki67hiBrdUhi cells in CM/CD4 T cell populations, based on their expression of CCR7, PD-1, and CD150, is also shown. (B) Pooled data showing the percentage of active caspase-3+ cells in the naive and CM subpopulations from noninfected (n = 7; white bars) and chronic SIV-infected RMs (n = 13; gray bars). (C) Pooled data showing the relative frequency (%) of PD-L1lo, PD-L1dim, and PD-L1hiCD20hiCD3lo B cells in SIV– (n = 10) and chronic SIV-infected LNs (n = 10 for low percentage of TFH cells and n = 4 for high percentage of TFH cells). (B and C) In the box-and-whiskers plot, box size represents the limits of data for the second and third quartiles, with medians shown as bars. Whiskers define the minimum and maximum of the data presented. P values were calculated using the Mann-Whitney U test. *P < 0.0001. (D) The relative expression of the S1PR1 mRNA in sorted cells from acute SIV-infected (n = 3; LN tissues) and chronic SIV-infected RMs, with low percentage of TFH cells (n = 3; LN tissues) and high percentage of TFH cells (n = 7; LN tissues), is shown. The normalized CT value for CD28hiCD95hiCCR7hiPD-1lo cells was assigned a value of 1, and the fold change over this value for the populations tested is shown.