Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging

Sage, Peter T.; Tan, Catherine L.; Freeman, Gordon J.; Haigis, Marcia C.; Sharpe, Arlene H.

doi:10.1016/j.celrep.2015.06.015

Cited by 110 publications

(122 citation statements)

References 29 publications

(47 reference statements)

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“…This is seen most clearly when we compare the Th1 to Tfh ratios as demonstrated in Figure 5E, where most of the ratios from aged cohorts are less than 2 and those from young cohorts range to over 50. Our results confirm those of Sage and colleagues [49] who also reported similar enhancement of the Tfh population in aged mice. This difference in Th subset distribution between young and aged groups could account for the fact that aging has a greater impact on the generation of lung-homing Th1 effectors rather than on Tfh cells and antibody production.…”

Section: Discussionsupporting

confidence: 93%

Vaccine efficacy and T helper cell differentiation change with aging

et al. 2016

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Influenza and pneumonia are leading causes of death in elderly populations. With age, there is an increased inflammatory response and slower viral clearance during influenza infection which increases the risk of extended illness and mortality. Here we employ a preclinical murine model of influenza infection to examine the protective capacity of vaccination with influenza nucleoprotein (NP). While NP vaccination reduces influenza-induced lung inflammation in young mice, aged mice do not show this reduction, but are protected from influenza-induced mortality. Aged mice do make a significant amount of NP-specific IgG and adoptive transfer experiments show that NP antibody can protect from death but cannot reduce lung inflammation. Furthermore, young but not aged vaccinated mice generate significant numbers of NP-specific T cells following subsequent infection and few of these T cells are found in aged lungs early during infection. Importantly, aged CD4 T cells have a propensity to differentiate towards a T follicular helper (Tfh) phenotype rather than a T helper 1 (Th1) phenotype that predominates in the young. Since Th1 cells are important in viral clearance, reduced Th1 differentiation in the aged is critical and could account for some or all of the age-related differences in vaccine responses and infection resolution.

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Section: Discussionsupporting

confidence: 93%

Vaccine efficacy and T helper cell differentiation change with aging

et al. 2016

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“…3a and Supplementary Fig. 2a), as previous studies performed181920. Both CD4 + CXCR5 hi PD-1 hi and CD4 + CXCR5 hi ICOS hi Tfh cells expressed the highest levels of Tfh-associated molecules CXCR5, PD-1 and ICOS, as well as the memory/activation marker CD44, compared with the other three subsets (Fig.…”

Section: Resultssupporting

confidence: 82%

Characterization of T follicular helper cells in allogeneic normal pregnancy and PDL1 blockage-induced abortion

Zeng

Liu

Zhang

et al. 2016

Sci Rep

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A deeper understanding of the immunological events during pregnancy will provide novel insights into the pathogenesis of pregnancy complications. The fundamental function of T follicular helper (Tfh) cells is to provide cognate help to B cells. Dysregulations of Tfh-cell function and/or development can result in various immunological diseases. However, the role and characteristics of Tfh cells during pregnancy remain unknown. Herein, an allogeneic-normal-pregnant mouse model was used, and we found that the CD4+ T cells residing at the uterus and placenta (UP) displayed a Tfh-like phenotype; and the UP-derived CD4+CXCR5hiPD-1hi and CD4+CXCR5hiICOShi Tfh cells, which showed a memory/activation phenotype, reached their peak at mid-pregnancy. These Tfh cells were located abundantly in the uterus at mid-pregnancy, but greatly increased in the placenta at late-pregnancy. Furthermore, increased foetal resorption by PDL1 blockade correlated with enhanced accumulation of Tfh cells and upregulated expressions of ICOS and PD-1 on these cells. Collectively, our findings are the first to indicate that an adequate and balanced accumulation of Tfh cells during gestation is likely to help maintaining a successful pregnancy, whereas an excessively high level of these cells could lead to abortion.

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“…However, regulatory CD4 + T cells are also found within GCs,235 and recent studies have shown that a subset of CXCR5 + FoxP3 + CD4 + Treg cells, termed T follicular regulatory (Tfr) cells, are generated as immune responses are induced and localize to the GC to control the GC response 236, 237, 238. In mice, Tfr cells have been shown to reduce antibody production and the number of GC B cells, antigen‐specific B cells, and plasma cells 236, 237, 238, 239, 240, 241. Multiple stages of the B‐cell differentiation process are inhibited, from initial B‐cell activation to the generation of class‐switched B cells and plasma cells.…”

Section: Regulatory Cell Populations and Their Relationship To Bnab Imentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging

Cited by 110 publications

References 29 publications

Vaccine efficacy and T helper cell differentiation change with aging

Vaccine efficacy and T helper cell differentiation change with aging

Characterization of T follicular helper cells in allogeneic normal pregnancy and PDL1 blockage-induced abortion

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

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