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Donna L Farber

Publications and source records attributed to Donna L Farber.

At least 19 recordsLinked to original sources
PubMed2025

Guidelines for T cell nomenclature.

Advances in T cell biology have revealed heterogeneity among T cell populations that is not captured by existing general nomenclature. This issue has caused an ad hoc broadening of core T cell subset definitions and the invention of new subset designations that have not been uniformly delineated. To address this issue, in this Consensus Statement, we propose guidelines that serve three goals. First, they advocate that primary research reports define the experimental basis by which relevant subsets are designated in the methods section of each study. Second, they provide standardized definitions for existing subset designations in popular use, and common experimental criteria for defining each subset are noted. Last, they present an alternative 'modular nomenclature' paradigm. The newly proposed modular nomenclature eschews conceptualization of antigen-experienced T cells as belonging to a few idealized subsets, and the nomenclature instead simply indicates individual biological properties present in a T cell population with brief descriptors. Collectively, these guidelines intend to enhance transparency in the literature while facilitating clearer communication of findings and concepts to researchers, students and clinicians.

Terminology as Topic↗
PubMed2025

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.

The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.

Humans↗
PubMed2006

Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway.

The CD28/B7 costimulatory pathway is generally considered dispensable for memory T cell responses, largely based on in vitro studies demonstrating memory T cell activation in the absence of CD28 engagement by B7 ligands. However, the susceptibility of memory CD4 T cells, including central (CD62L(high)) and effector memory (T(EM); CD62L(low)) subsets, to inhibition of CD28-derived costimulation has not been closely examined. In this study, we demonstrate that inhibition of CD28/B7 costimulation with the B7-binding fusion molecule CTLA4Ig has profound and specific effects on secondary responses mediated by memory CD4 T cells generated by priming with Ag or infection with influenza virus. In vitro, CTLA4Ig substantially inhibits IL-2, but not IFN-gamma production from heterogeneous memory CD4 T cells specific for influenza hemagglutinin or OVA in response to peptide challenge. Moreover, IL-2 production from polyclonal influenza-specific memory CD4 T cells in response to virus challenge was completely abrogated by CTLA4Ig with IFN-gamma production partially inhibited. When administered in vivo, CTLA4Ig significantly blocks Ag-driven memory CD4 T cell proliferation and expansion, without affecting early recall and activation. Importantly, CTLA4Ig treatment in vivo induced a striking shift in the phenotype of the responding population from predominantly T(EM) in control-treated mice to predominantly central memory T cells in CTLA4Ig-treated mice, suggesting biased effects of CTLA4Ig on T(EM) responses. Our results identify a novel role for CD28/B7 as a regulator of memory T cell responses, and have important clinical implications for using CTLA4Ig to abrogate the pathologic consequences of T(EM) cells in autoimmunity and chronic disease.

Abatacept↗
PubMed2006

Human bone marrow: a reservoir for "enhanced effector memory" CD8+ T cells with potent recall function.

The role of human bone marrow (BM) CD8+ T cells in the immune response to viral Ags is poorly defined. We report here the identification and characterization of a functionally enhanced effector memory CD8+ T cell population (TEM) in the BM of patients undergoing total joint replacement for osteoarthritis. These BM-derived TEM differ strikingly from correlate cells in peripheral blood (PB), expressing elevated levels of CD27, HLA-DR, CD38, CD69, and unique patterns of chemokine receptors. Interestingly, while BM TEM have low levels of resting perforin and granzyme B, these molecules evidence profound up-regulation in response to TCR stimulation resulting in enhanced cytotoxic potential. Moreover, compared with the TEM subset in PB, BM CD8+ TEM cells demonstrate a more vigorous recall response to pooled viral Ags. Our results reveal that human BM serves as a repository for viral Ag-specific TEM with great therapeutic potential in vaccine development.

Aged↗
PubMed2006

Reshaping the past: Strategies for modulating T-cell memory immune responses.

Memory T cells are generated following an initial encounter with antigen, persist over the lifetime of an individual, and mediate rapid and robust functional responses upon antigenic recall. While immune memory is generally associated with protective immune response to pathogens, memory T cells can be generated to diverse types of antigens including autoantigens and alloantigens through homologous or crossreactive priming and comprise the majority of circulating T cells during adulthood. Memory T cells can therefore play critical roles in propagating and perpetuating autoimmune disease and in mediating allograft rejection, although the precise pathways for regulation of memory immune responses remain largely undefined. Moreover, evaluating and designing strategies to modulate memory T-cell responses are challenging given the remarkable heterogeneity of memory T cells, with different subsets predominating in lymphoid versus non-lymphoid tissue sites. In this review, we discuss what is presently known regarding the effect of current immunomodulation strategies on the memory T-cell compartment and potential strategies for controlling immunological recall.

Animals↗
PubMed2006

Divergent generation of heterogeneous memory CD4 T cells.

Mechanisms for the generation of memory CD4 T cells and their delineation into diverse subsets remain largely unknown. In this study, we demonstrate in two Ag systems, divergent generation of heterogeneous memory CD4 T cells from activated precursors in distinct differentiation stages. Specifically, we show that influenza hemagglutinin- and OVA-specific CD4 T cells activated for 1, 2, and 3 days, respectively, exhibit gradations of differentiation by cell surface phenotype, IFN-gamma production, and proliferation, yet all serve as direct precursors for functional memory CD4 T cells when transferred in vivo into Ag-free mouse hosts. Using a conversion assay to track the immediate fate of activated precursors in vivo, we show that day 1- to 3-activated cells all rapidly convert from an activated phenotype (CD25(high)IL-7R(low)CD44(high)) to a resting memory phenotype (IL-7R(high)CD25(low)CD44(high)) 1 day after antigenic withdrawal. Paradoxically, stable memory subset delineation from undifferentiated (day 1- to 2-activated) precursors was predominantly an effector memory (CD62L(low)) profile, with an increased proportion of central memory (CD62L(high)) T cells arising from more differentiated (day 3-activated) precursors. Our findings support a divergent model for generation of memory CD4 T cells directly from activated precursors in multiple differentiation states, with subset heterogeneity maximized by increased activation and differentiation during priming.

Amino Acid Sequence↗
PubMed2006

Committed to memory: lineage choices for activated T cells.

The mechanisms for the generation of memory T cells and their delineation into heterogeneous subsets remain unknown. The linear model for memory T-cell generation from differentiated effector cells has been favored, although there is evidence that memory T cells can emerge directly from naive T cells undergoing homeostatic expansion and from activated T cells lacking effector functions. Here, we discuss the evidence from diverse studies of memory generation that support a new 'intersecting pathway' model for memory T-cell generation in which antigen-driven effector differentiation and homeostasis-driven memory differentiation follow distinct but analogous pathways. Antigen withdrawal during effector differentiation enables intersection with the memory pathway through a pre-memory intermediate, and memory heterogeneity is influenced by homeostasis, migration and persistence in vivo.

Animals↗
PubMed2006

Abrogation of recurrent autoimmunity in the NOD mouse: A critical role for host interleukin 4.

BACKGROUND: We previously established a clinically relevant strategy to abrogate recurrent autoimmunity and enable long-term islet graft survival, involving antilymphocyte serum (ALS)-depletion of recipient T cells and intraportal administration of donor pancreatic lymph node cells (PLNCs) along with islet grafts. In this study, we investigated whether Th2 cytokines were required for the tolerizing ability of ALS/PLNC treatment in islet transplantation. METHODS: ALS-treated diabetic NOD recipient mice, and NOD recipient mice deficient in interleukin 4 (IL-4-/-) or 10 (IL-4/10-/-) were transplanted with NOR or NOD.scid islets intraportally along with donor PLNC. Blood glucose levels were monitored to access graft function, sections of graft-bearing livers were histologically examined, and ELISPOT assays were used to assess cytokine profile and frequency of islet-reactive CD4 T cells. RESULTS: We found that ALS/PLNC was not effective in prolonging islet graft survival in diabetic NOD hosts deficient in either IL-4 (NOD.IL-4-/-) or in IL-4 and IL-10 (NOD.IL4-/-/10-/-) (mean survival time, 36 days), contrasting the long-term survival of islet grafts in wild-type NOD mice (mean survival time, > 80 days). In contrast, PLNC deficient in IL-4 promoted long-term graft survival in wild-type NOD hosts similar to that in wild-type PLNC. In wild-type NOD recipients of either wild-type PLNC or IL-4-/- PLNC, the host autoantigen-specific CD4 T cells produced predominately IL-4 coincident with long-term graft survival, whereas, in NOD.IL-4-/- recipients with rejected grafts, the autoreactive T cells produced interferon gamma and low amounts of IL-4. CONCLUSIONS: These data demonstrate that abrogation of recurrent autoimmunity requires host IL-4 and that manipulation of the autoreactive cytokine profile in long-term diabetes may be an effective strategy for islet transplant therapies.

Animals↗
PubMed2005

Anti-CD3 priming generates heterogeneous antigen-specific memory CD4 T cells.

Anti-CD3 activation of peripheral T cells is used in adoptive immunotherapy for cancer and HIV infection, but the long-term fate of anti-CD3-primed T cells in vivo is not known. In this study, we demonstrate that anti-CD3-mediated activation of influenza hemagglutinin (HA)-specific TCR-transgenic CD4 T cells results in generation of a long-lived HA-specific memory CD4 T cell population when transferred into lymphocyte-deficient and intact mouse hosts. This anti-CD3-primed memory population is indistinguishable from HA peptide-primed memory CD4 T cells in terms of phenotype, rapid recall function, and enhanced proliferative capacity. Moreover, anti-CD3 priming generates phenotypically heterogeneous memory subsets in lymphoid and non-lymphoid sites. Our results suggest that anti-CD3 has potential efficacy in generating memory responses in adoptive immunotherapies and vaccines and that the tissue distribution and maintenance of heterogeneous lymphoid and non-lymphoid memory T cell subsets are a stochastic process that can occur independent of antigen or TCR specificity.

Animals↗
PubMed2005

Modulation of memory CD4 T cell function and survival potential by altering the strength of the recall stimulus.

Optimization of long term immunity depends on the functional persistence of memory T cells; however, there are no defined strategies for promoting memory T cell function and survival. In this study, we hypothesized that varying the strength of the recall stimulus could modulate the function and survival potential of memory CD4 T cells. We tested the ability of peptide variants of influenza hemagglutinin (HA) exhibiting strong and weak avidity for an HA-specific TCR, to modulate HA-specific memory CD4 T cells in vitro and in vivo. In vitro stimulation with a weak avidity peptide (L115) uncoupled memory CD4 T proliferation from effector cytokine production with low apoptosis, whereas stimulation with a strong avidity peptide (Y117) fully recalled memory T cell functions but triggered increased apoptosis. To determine how differential recall would affect memory T cells in vivo, we boosted BALB/c hosts of transferred, CFSE-labeled HA-specific memory CD4 T cells with native HA, Y117, and L115 variant peptides and found differences in early Ag-driven memory T cell proliferation and IL-7R expression, with subsequent changes in memory T cell yield. High avidity boosting resulted in rapid proliferation, extensive IL-7R down-regulation, and the lowest yield of HA-specific memory cells, whereas low avidity boosting triggered low in vivo proliferation, maintenance of IL-7R expression, and the highest memory T cell yield. Our results indicate that memory CD4 T cell function and survival can be modulated at the recall level, and can be optimized by low level stimulation that minimizes apoptosis and enhances responses to survival factors.

Animals↗
PubMed2005

Novel phenotypes and migratory properties distinguish memory CD4 T cell subsets in lymphoid and lung tissue.

Memory T cells are heterogeneous in expression of lymph node homing receptors, delineating "central-memory" (TCM, CD62Lhi/CCR7+) and "effector-memory" (TEM, CD62Llo/CCR7-) subsets that migrate to lymphoid and non-lymphoid tissues, respectively. It is not known how these subsets arise or how homing receptor expression and tissue origin determine their functional and migratory properties. Here, we investigated the role of CD62L expression in the generation, function, distribution and migration of heterogeneous memory CD4 T cells specific for influenza hemagglutinin (HA). We found that CD62Lhi and CD62Llo memory subsets are generated independent of CD62L expression by the activated precursor, and both subsets distribute into spleen and lung. Functionally, spleen- and lung-derived CD62L memory subsets produce effector cytokines at similar kinetics but differ strikingly in cell surface phenotype and migration: the CD62Llo memory subset expresses a classic memory phenotype (CD45RBlo/CD44hi/CD11a(hi)), while the CD62Lhi subset expresses an unconventional phenotype (CD45RBhi/CD44int/CD11a(int)), defining a new polyclonal memory subset. The CD62Lhi subset also trafficked more efficiently than CD62Llo cells into lymph nodes; however, only lung but not spleen CD62Llo memory T cells homed to lung. Our results reveal novel phenotypic heterogeneity of memory CD4 T cells co-segregating with CD62L expression and tissue-specific tropism of non-lymphoid memory CD4 T cells.

Animals↗
PubMed2004

Regulation of CD103 expression by CD8+ T cells responding to renal allografts.

CD103 is an integrin with specificity for the epithelial cell-specific ligand, E-cadherin. Recent studies indicate that CD103 expression endows peripheral CD8 cells with a unique capacity to access the epithelial compartments of organ allografts. In the present study we used a nonvascularized mouse renal allograft model to 1) define the mechanisms regulating CD103 expression by graft-infiltrating CD8 effector populations, and 2) identify the cellular compartments in which this occurs. We report that CD8 cells responding to donor alloantigens in host lymphoid compartments do not initially express CD103, but dramatically up-regulate CD103 expression to high levels subsequent to migration to the graft site. CD103+CD8+ cells that infiltrated renal allografts exhibited a classic effector phenotype and were selectively localized to the graft site. CD8 cells expressing low levels of CD103 were also present in lymphoid compartments, but three-color analyses revealed that these are almost exclusively of naive phenotype. Adoptive transfer studies using TCR-transgenic CD8 cells demonstrated that donor-specific CD8 cells rapidly and uniformly up-regulate CD103 expression following entry into the graft site. Donor-specific CD8 cells expressing a dominant negative TGF-beta receptor were highly deficient in CD103 expression following migration to the graft, thereby implicating TGF-beta activity as a dominant controlling factor. The relevance of these data to conventional (vascularized) renal transplantation is confirmed. These data support a model in which TGF-beta activity present locally at the graft site plays a critical role in regulating CD103 expression, and hence the epitheliotropism, of CD8 effector populations that infiltrate renal allografts.

Animals↗
PubMed2004

Signaling control of memory T cell generation and function.

Memory T cells exhibit low activation thresholds and mediate rapid effector responses when recalled by antigen; contrasting the higher activation threshold, slower responses and predominant IL-2 production by naive T cells. While the sequence of intracellular events coupling the T cell-receptor (TCR) to naive T cell activation is well characterized, biochemical control of memory T cell differentiation and function remains undefined. In this review, we will discuss recent developments in T cell-receptor signal transduction as they pertain to memory T cells, and will discuss how signal dampening may drive memory generation, and more efficient spatial organization of signaling molecules may promote rapid recall responses.

Animals↗
PubMed2004

Memory T cells in transplantation: generation, function, and potential role in rejection.

The adaptive immune system is endowed with long-lived memory to recall previous antigen encounters and respond more effectively to them. Memory immune responses are mediated by antigen-specific memory T lymphocytes that exhibit enhanced function compared with naïve T cells that have never encountered antigen. While the generation of memory T cells specific for pathogens is beneficial in providing protective immunity, memory T cells specific for alloantigens can be deleterious to the recipient of a transplanted organ. In graft rejection, memory T cells mediate accelerated, "second-set" rejection and their presence has been associated with increased propensity for early rejection. Recent findings have demonstrated that alloreactive memory T cells can be generated via exposure to alloantigens, as well as stimuli that are cross-reactive with alloantigens, and are therefore likely present in "naïve" individuals. This review focuses on the characteristics of memory T cells which make them of special interest to the transplant community, including differential activation requirements, broad homing properties, and resistance to tolerance induction. The multiple ways in which memory T cells can contribute to early and late graft rejection are discussed, as well as potential targets for combating alloreactive memory to be considered in the future design of tolerance induction strategies.

Animals↗
PubMed2004

Long-term islet graft survival in NOD mice by abrogation of recurrent autoimmunity.

Islet transplantation has great potential for curing type 1 diabetes; however, long-term islet survival using conventional immunosuppression remains elusive. We present a novel strategy for inducing long-lasting islet graft survival in diabetic NOD mice in the absence of posttransplant immunosuppression by initial treatment with antilymphocyte serum (ALS) followed by coadministration of donor pancreatic lymph node cells (PLNCs). When treated with ALS/PLNC, diabetic NOD mice become normoglycemic and tolerated minor antigen-disparate islet grafts for >100 days and syngeneic islet grafts indefinitely. Donor T-cells are required for graft prolongation, and tolerant hosts have long-term donor T-cell chimerism. Strikingly, host autoreactive T-cells from mice with long-surviving islet grafts predominantly produce interleukin-4, whereas autoreactive T-cells from mice that rejected their islet grafts predominantly produce interferon-gamma. We thus demonstrate a clinically relevant approach for ablation of recurrent autoimmunity in islet transplantation, involving donor lymphocyte-driven alteration of pathogenic autoreactive T-cells.

Animals↗