Instructor, Medicine - Immunology & Rheumatology
Boards, Advisory Committees, Professional Organizations
Postdoctoral Committee, Immunology (2015 - 2019)
Impaired vaccine responses in older individuals are associated with alterations in both the quantity and quality of the T-cell compartment with age. As reviewed herein, the T-cell response to vaccination requires a fine balance between the generation of inflammatory effector T cells versus follicular helper T (TFH) cells that mediate high-affinity antibody production in tandem with the induction of long-lived memory cells for effective recall immunity. During aging, we find that this balance is tipped where T cells favor short-lived effector but not memory or TFH responses. Consistently, vaccine-induced antibodies commonly display a lower protective capacity. Mechanistically, multiple, potentially targetable, changes in T cells have been identified that contribute to these age-related defects, including posttranscription regulation, T-cell receptor signaling, and metabolic function. Although research into the induction of tissue-specific immunity by vaccines and with age is still limited, current mechanistic insights provide a framework for improved design of age-specific vaccination strategies that require further evaluation in a clinical setting.
View details for DOI 10.1016/j.jaci.2020.03.017
View details for PubMedID 32386655
Adjuvant chemotherapy in breast cancer patients causes immune cell depletion at an age when the regenerative capacity is compromised. Successful regeneration requires the recovery of both quantity and quality of immune cell subsets. Although immune cell numbers rebound within a year after treatment, it is unclear whether overall compositional diversity is recovered. We investigated the regeneration of immune cell complexity by comparing peripheral blood mononuclear cells from breast cancer patients ranging from 1-5 years after chemotherapy with those of age-matched healthy controls using mass cytometry and T cell receptor sequencing. These data reveal universal changes in patients' CD4+ T cells that persisted for years and consisted of expansion of Th17-like CD4 memory populations with incomplete recovery of CD4+ naive T cells. Conversely, CD8+ T cells fully recovered within a year. Mechanisms of T cell regeneration, however, were unbiased, as CD4+ and CD8+ T cell receptor diversity remained high. Likewise, terminal differentiated effector memory cells were not expanded, indicating that regeneration was not driven by recognition of latent viruses. These data suggest that, while CD8+ T cell immunity is successfully regenerated, the CD4 compartment may be irreversibly affected. Moreover, the bias of CD4 memory toward inflammatory effector cells may impact responses to vaccination and infection.
View details for DOI 10.1172/jci.insight.134569
View details for PubMedID 32102986
By 2050, there will be over 1.6 billion adults aged 65 years and older, making age-related diseases and conditions a growing public health concern. One of the leading causes of death in the ageing population is pathogenic infections (e.g. influenza, Streptococcus pneumoniae). This age-dependent susceptibility to infection has been linked to a reduced ability of the ageing immune system to mount protective responses against infectious pathogens, as well as to vaccines against these pathogens. The primary immune response that promotes protection is the production of antibodies by B cells - a response that is directly mediated by T follicular helper (TFH) cells within germinal centers (GCs) in secondary lymphoid tissues. In this review, we will summarize the current knowledge on the development and functionality of TFH cells, the use of circulating TFH (cTFH) cells as vaccine biomarkers, and the influence of age on these processes. Moreover, we will discuss the strategies for overcoming TFH cell dysfunction to improve protective antibody responses in the ageing human population.
View details for PubMedID 30185614
One of the most prominent immunological changes during human aging is the alteration in CD8 T-cell subset distribution, predominated by a loss of na´ve CD8 T cells. The molecular mechanisms that contribute to the loss of na´ve CD8 T-cells during aging remain unclear. Considering that many CD8 T-cell functions are influenced by microRNAs (miRNAs), we explored miRNA expression profiling to identify novel dysfunctions that contribute to na´ve CD8 T-cell loss during aging. Here, we describe age-dependent miRNA expression changes in na´ve, central memory, and effector memory CD8 T-cell subsets. Changes in old na´ve CD8 T-cells partially resembled those driven by an underlying shift in cellular differentiation toward a young central memory phenotype. Pathways enriched for targets of age-dependent miRNAs included FOXO1, NF-?B, and PI3K-AKT signaling. Transcriptome analysis of old na´ve CD8 T-cells yielded corresponding patterns that correlated to those seen with reduced FOXO1 or altered NF-?B activities. Of particular interest, IL-7R expression, controlled by FOXO1 signaling, declines on na´ve CD8 T cells with age and directly correlates with the frequencies of na´ve CD8 T cells. Thus, age-associated changes in miRNA networks may ultimately contribute to the failure in CD8 T-cell homeostasis exemplified by the loss in na´ve cells.
View details for PubMedID 30488559
Aging is associated with an increased susceptibility to infection and a failure to control latent viruses thought to be driven, at least in part, by alterations in CD8 T cell function. The aging T cell repertoire is characterized by an accumulation of effector CD8 T cells, many of which express the negative regulatory receptor CD85j. To define the biological significance of CD85j expression on CD8 T cells and to address the question whether presence of CD85j in older individuals is beneficial or detrimental for immune function, we examined the specific attributes of CD8 T cells expressing CD85j as well as the functional role of CD85j in antigen-specific CD8 T cell responses during immune aging. Here, we show that CD85j is mainly expressed by terminally differentiated effector (TEMRAs) CD8 T cells, which increase with age, in cytomegalovirus (CMV) infection and in males. CD85j+ CMV-specific cells demonstrate clonal expansion. However, TCR diversity is similar between CD85j+ and CD85j- compartments, suggesting that CD85j does not directly impact the repertoire of antigen-specific cells. Further phenotypic and functional analyses revealed that CD85j identifies a specific subset of CMV-responsive CD8 T cells that coexpress a marker of senescence (CD57) but retain polyfunctional cytokine production and expression of cytotoxic mediators. Blocking CD85j binding enhanced proliferation of CMV-specific CD8 T cells upon antigen stimulation but did not alter polyfunctional cytokine production. Taken together, these data demonstrate that CD85j characterizes a population of "senescent," but not exhausted antigen-specific effector CD8 T cells and indicates that CD85j is an important checkpoint regulator controlling expansion of virus-specific T cells during aging. Inhibition of CD85j activity may be a mechanism to promote stronger CD8 T cell effector responses during immune aging.
View details for PubMedID 28659925
With reducedthymic activity, the population of naive T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naive CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naive CD4 T-cell aging is associated with a partial loss of this unbiased multipotency. We find that naive CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor beta (TGFbeta) stimulation is enhanced with age due to an upregulation of the TGFbetaR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naive CD4 T cells display altered transcription factor profiles in response to T-cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging-associated changes in the transcription factor profile favor TH9 commitment.
View details for DOI 10.1111/acel.12957
View details for PubMedID 31264370
To investigate the alterations in both structure and contractile responsiveness of ocular ciliary artery (OCA) in spontaneously hypertensive rat (SHR).In this experiment, 20-week-old male SHR and Wistar Kyoto rat (WKY) were studied. The heart rate (HR), the blood pressure (BP; the systolic BP and the diastolic BP) of rats with an electronic sphygmomanometer were measured. Vascular morphometry and isometric tension measurement were used to investigate the alterations in structure and contractility of OCA.A general narrowing of OCAs was observed in SHR compared to the control WYK. In SHR, the media of OCAs were thicker, the luminal diameters were smaller, and the media-to-lumen ratios were higher when compared with WKY (P<0.05). The contractions of OCAs evoked by norepinephrine were smaller in SHR compared to control (P<0.05). Then, OCAs were pretreated with iberiotoxin, L-NAME, or indomethacin 30min before norepinephrine-induced contraction. Iberiotoxin (0.1 Ámol/L) has not changed the norepinephrine-induced contractions in OCAs from both groups. However, L-NAME (100 Ámol/L) increased the vasoconstrictions, the increased extents were similar in SHR and WKY (P>0.05). Indomethacin (10 Ámol/L) decreased the contractions induced by norepinephrine in OCAs from WKY (P<0.05), but did not change those contractions in vessels from SHR (P>0.05).Our results demonstrate that the structure and function of OCAs are altered in hypertension. OCAs from SHR are remodeled with decreased lumen diameter and increased media-to-lumen ratio. Moreover, the contractile responsiveness of OCAs from SHR is diminished due to the disruption of vasoconstrictive effect of prostaglandins.
View details for PubMedID 30918801
View details for PubMedCentralID PMC6423402
Generation of protective immunity to infections and vaccinations declines with age. Studies in healthy individuals have implicated reduced miR-181a expression in Tácells as contributing to this defect. To understand the impact of miR-181a expression on antiviral responses, we examined LCMV infection in mice with miR-181ab1-deficient Tácells. We found that miR-181a deficiency delays viral clearance, thereby biasing the immune response in favor of CD4 over CD8 Tácells. Antigen-specific CD4 Tácells in mice with miR-181a-deficient Tácells expand more and have a broader TCR repertoire with preferential expansion of high-affinity Tácells than in wild-type mice. Importantly, generation of antigen-specific miR-181a-deficient CD8 effector Tácells is particularly impaired, resulting in lower frequencies of CD8 Tácells in the liver even at time points when the infection has been cleared. Consistent with the mouse model, CD4 memory Tácells in individuals infected with West Nile virus at older ages tend to be more frequent and of higher affinity.
View details for DOI 10.1016/j.celrep.2019.10.044
View details for PubMedID 31747595
Immune aging is a multi-faceted process that manifests as reduced competence to fight infections and malignant cells, as well as diminished tissue repair, unprovoked inflammation, and increased autoreactivity. The aging adaptive immune system, with its high complexity in functional cell subpopulations and diversity of B- and T-cell receptors, has to cope with the challenge of maintaining homeostasis while responding to exogenous stimuli and compensating for reduced generative capacity. With thymic involution, na´ve T cells begin to function as quasi-stem cells and maintain the compartment through peripheral homeostatic proliferation that shapes the T-cell repertoire through peripheral selection and the activation of differentiation pathways. Similarly, reduced generation of early B-cell progenitors alters the composition of the peripheral B-cell compartment with the emergence of a unique, auto-inflammatory B-cell subset, termed age-associated B cells (ABCs). These changes in T- and B-cell composition and function are core manifestations of immune aging.
View details for DOI 10.1053/j.seminhematol.2016.10.003
View details for Web of Science ID 000393445800006
View details for PubMedID 28088985
Mitochondrial transcription factor A (TFAM) had previously been shown to act as a damage associated molecular pattern with the ability to enhance CpG-A phosphorothioate oligodeoxynucleotide (ODN)-mediated stimulation of IFN? production from human plasmacytoid dendritic cells. Examination of the mechanism by which TFAM might influence CpG ODN mediated innate immune responses revealed that TFAM binds directly, tightly and selectively to the structurally related CpG-A, -B, and -C ODN. TFAM also modulated the ability of the CpG-B or -C to stimulate the production of antibodies from human B cells. TFAM showed a dose-dependent modulation of CpG-B, and -C -induced antibody production from human B cells in vitro, with enhancement of high dose and inhibition of low doses of CpG stimulation. This effect was linked to the ability of TFAM to directly inhibit the binding of CpG ODNs to B cells, in a manner consistent with the relative binding affinities of TFAM for the ODNs. These data suggest that TFAM alters the free concentration of the CpG available to stimulate B cells by sequestering this ODN in a TFAM-CpG complex. Thus, TFAM has the potential to decrease the pathogenic consequences of exposure to natural CpG-like hypomethylated DNA in vivo, as well as such as that found in traumatic injury, infection, autoimmune disease and during pregnancy.
View details for DOI 10.1371/journal.pone.0157157
View details for Web of Science ID 000377563000098
View details for PubMedID 27280778
The absence of immunoglobulin A (IgA) in the intestinal tract renders young infants highly susceptible to enteric infections. However, mediators of initial IgA induction in this population are undefined. We determined the temporal acquisition of plasma cells by isotype and expression of T cell-independent (TI) and -dependent (TD) IgA class switch factors in the human intestinal tract during early infancy. We found that IgA plasma cells were largely absent in the infant intestine until after 1 month of age, approaching adult densities later in infancy than both IgM and IgG. The restricted development of IgA plasma cells in the first month was accompanied by reduced expression of the TI factor a proliferation-inducing ligand (APRIL) and its receptors TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) and B cell maturation antigen (BCMA) within isolated lymphoid follicles (ILFs). Moreover, both APRIL and BCMA expression strongly correlated with increasing IgA plasma cell densities over time. Conversely, TD mediators (CD40 ligand (CD40L) and CD40) were expressed within ILFs before 1 month and were not associated with IgA plasma cell generation. In addition, preterm infants had lower densities of IgA plasma cells and reduced APRIL expression compared with full-term infants. Thus, blunted TI responses may contribute to the delayed induction of intestinal IgA during early human infancy.
View details for DOI 10.1038/mi.2013.64
View details for Web of Science ID 000334923700003
View details for PubMedID 24045575
View details for PubMedCentralID PMC3959635
Among HIV-exposed infants in resource-limited countries, 8-12% are infected postnatally by breastfeeding. However, most of those uninfected at birth remain uninfected over time despite daily exposure to HIV in breast milk. Thus, we assessed the HIV-inhibitory activity of breast milk.We measured cross-clade neutralization in activated PBMC of Ugandan subtype A (92UG031) and D (92UG005) primary HIV by breast milk or purified milk IgG and IgA from 25 HIV-infected Ugandan women. Isotype-specific antigen recognition was resolved by immunoblot. We determined HIV subtype from envelope population sequences in cells from 13 milk samples by PCR.Milk inhibited p24 production by ?50% (dose-dependent) by subtype A (21/25; 84%) and subtype D (11/25; 44%). IgG consistently reacted with multiple HIV antigens, including gp120/gp41, but IgA primarily recognized p24 alone. Depletion of IgG (ná=á5), not IgA, diminished neutralization (mean 78á▒á33%) that was largely restored by IgG repletion. Mothers infected with subtype A more effectively neutralized subtype A than D.Breast milk from HIV-infected women showed homotypic and cross-subtype neutralization of HIV by IgG-dependent and -independent mechanisms. These data direct further investigations into mechanisms of resistance against postnatal transmission of HIV to infants from their mothers.
View details for DOI 10.1016/j.jinf.2013.11.002
View details for Web of Science ID 000331712100008
View details for PubMedID 24239588
During an inflammatory response, resident and newly recruited tissue macrophages adhere to extracellular matrix and cell-bound integrin ligands. This interaction induces the expression of pro-inflammatory mediators that include matrix metalloproteinases (MMPs). Arhgef1 is an intracellular signaling molecule expressed by myeloid cells that normally attenuates murine macrophage MMP production in vivo and in vitro after cell culture on the extracellular matrix protein, fibronectin. In this study, we have extended the characterization of this fibronectin-induced Arhgef1-regulated signaling pathway in both human and murine myeloid cells. Our results show that MMP9 production by fibronectin-stimulated monocytes and macrophages depends on autocrine thromboxane receptor signaling and that under normal conditions, this signaling pathway is attenuated by Arhgef1. Finally, we show that the expression of ARHGEF1 by human peripheral blood monocytes varies between individuals and inversely correlates with fibronectin-mediated MMP9 production.
View details for DOI 10.1074/jbc.M111.282772
View details for Web of Science ID 000298645500024
View details for PubMedID 22086927
View details for PubMedCentralID PMC3247948