Biomedical subjects

Mojgan Ahmadzadeh

Publications and source records attributed to Mojgan Ahmadzadeh.

10 recordsLinked to original sources

PubMed2006

Modulation by IL-2 of CD70 and CD27 expression on CD8+ T cells: importance for the therapeutic effectiveness of cell transfer immunotherapy.

Proper T cell function relies on the integration of signals delivered by Ag, cytokine, and costimulatory receptors. In this study, the interactions between IL-2, CD27, and its ligand CD70 and their effects on human T cell function were examined. Unstimulated CD8(+) T cells expressed relatively low levels of CD70 and high levels of CD27. Incubation in vitro with high doses of IL-2 (3,000 IU/ml) or administration of IL-2 in vivo resulted in substantial up-regulation of CD70 expression and the concomitant loss of cell surface CD27 expression on CD8(+) cells. Withdrawal of IL-2 from activated CD8(+) T cells that had been maintained in IL-2 resulted in a reversal of the expression of these two markers, whereas reciprocal changes were seen following treatment of PBMCs with IL-2. The proliferation observed in cells stimulated with IL-2 primarily occurred in a subset of the CD70(+)CD8(+) T cells that up-regulated IL-2 receptor expression but did not occur in CD70(-)CD8(+) T cells. Blocking CD70 resulted in a significant reduction of T cell proliferation induced by high-dose IL-2, indicating that the interaction of CD70 with CD27 played a direct role in T cell activation mediated by IL-2. Finally, studies conducted on tumor-infiltrating lymphocyte (TIL) samples that were administered to melanoma patients indicated that the size of the pool of CD27(+)CD8(+) T cells in bulk TILs was highly associated (p = 0.004) with the ability of these TILs to mediate tumor regression following adoptive transfer.

Antigens, CD↗

PubMed2006

Interleukin-2-dependent mechanisms of tolerance and immunity in vivo.

IL-2 is a critical T cell growth factor in vitro, but predominantly mediates tolerance in vivo. IL-2 is mainly produced by CD4(+) Th cells, but the role of Th cell-derived IL-2 in vivo is controversial. We demonstrate that during immunity to a tumor/self-Ag, the predominant role of Th cell-derived IL-2 was to maintain IL-2Ralpha (CD25) on CD4(+) T regulatory cells (T(reg)), which resulted in their maintenance of the T(reg) cell lineage factor, Forkhead/winged helix transcription factor (Foxp3), and tolerance. However, in the absence of T(reg) cells, Th cell-derived IL-2 maintained effector T cells and caused autoimmunity. IL-2R signaling was indispensable for T(reg) cell homeostasis and efficient suppressor function in vivo, but, surprisingly, was not required for their generation, because IL-2(-/-) and CD25(-/-) mice both contained Foxp3(+) T cells in the periphery. IL-2R signaling was also important for CD8(+) T cell immunity, because CD25(-/-) tumor-reactive CD8(+) T cells failed to affect established tumors. Conversely, IL-2R signaling was not required for Th cell function. Lastly, administration of anti-IL-2 plus exogenous IL-15 to tumor-bearing mice enhanced the adoptive immunotherapy of cancer. Therefore, Th cell-derived IL-2 paradoxically controls both tolerance and immunity to a tumor/self-Ag in vivo.

Animals↗

PubMed2006

High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT.

Regulatory T cells (T(reg)s) that constitutively express FOXP3 are instrumental to the maintenance of tolerance and may suppress graft-versus-host disease (GVHD) in humans. To determine whether regulatory T cells in allogeneic stem cell transplants (SCTs) ameliorate GVHD after transplantation, we quantitated the coexpression of FOXP3 on CD4(+) T cells in 32 donor SCTs infused into HLA-matched siblings and examined GVHD incidence in respective recipients. High CD4(+)FOXP3(+) T-cell count in the donor was associated with a reduced risk of GVHD. We monitored T(reg)s during immune reconstitution in 21 patients with leukemia undergoing a T-cell-depleted allogeneic SCT. Early after SCT, there was a significant expansion in the CD4(+)FOXP3(+) T-cell compartment. A low CD4(+)FOXP3(+) T-cell count early after SCT (day 30) was associated with an increased risk of GVHD, and the ratio of CD4(+)FOXP3(+) T cells to CD4(+)CD25(+)FOXP3(-) T cells was significantly reduced in patients with GVHD, suggesting diminished control of effector T cells. Our findings suggest that graft T(reg) content may predict for risk of GVHD after SCT. Determining the T(reg) levels in the donor and manipulating T(reg)s early after transplantation may provide a new approach to controlling GVHD.

Adolescent↗

PubMed2005

IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients.

Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+ CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+ CD25(hi) T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+ CD25(hi) T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+ CD25(hi) T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+ CD25(hi) Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration.

Adolescent↗

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

TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells.

TGF-beta1 is a potent immunoregulatory cytokine. However, its impact on the generation and effector function of Ag-specific human effector memory CD8 T cells had not been evaluated. Using Ag-specific CD8 T cells derived from melanoma patients immunized with the gp100 melanoma Ag, we demonstrate that the addition of TGF-beta1 to the initial Ag activation cultures attenuated the gain of effector function by Ag-specific memory CD8 T cells while the phenotypic changes associated with activation and differentiation into effector memory were comparable to control cultures. These activated memory CD8 T cells consistently expressed lower mRNA levels for T-bet, suggesting a mechanism for TGF-beta1-mediated suppression of gain of effector function in memory T cells. Moreover, TGF-beta1 induced a modest expression of CCR7 on Ag-activated memory CD8 T cells. TGF-beta1 also suppressed cytokine secretion by Ag-specific effector memory CD8 T cells, as well as melanoma-reactive tumor-infiltrating lymphocytes and CD8 T cell clones. These results demonstrate that TGF-beta1 suppresses not only the acquisition but also expression of effector function on human memory CD8 T cells and tumor-infiltrating lymphocytes reactive against melanoma, suggesting that TGF-beta1-mediated suppression can hinder the therapeutic benefits of vaccination, as well as immunotherapy in cancer patients.

Cell Line, Tumor↗

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↗

PubMed2002

Functional plasticity of an antigen-specific memory CD4 T cell population.

The protective nature of memory immune responses is attributed largely to terminally differentiated memory T cells that retain memory of the antigen via the antigen receptor and memory of the effector functions that initially cleared the pathogen. It is not known whether a given population of antigen-specific memory T cells is endowed with functional flexibility to provide protective responses against antigens reencountered in different immunological contexts. Here, we examine functional properties of influenza hemagglutinin (HA)-specific memory CD4 T cells recovered from adoptive hosts that received in vitro-activated HA-specific T cell receptor-transgenic CD4 T cells 2 months to 1 year previously. We demonstrate that this HA-specific memory CD4 T cell population bearing a clonal T cell receptor can produce predominantly T helper 1 or T helper 2 effector cytokines depending on the nature of the recall stimulus. Our findings reveal remarkable functional plasticity within an antigen-specific memory T cell population and have direct implications for modulating memory T cell function in vaccine design and treatments for autoimmune diseases.

Adoptive Transfer↗

PubMed2002

Dissecting the complexity of the memory T cell response.

Memory immune responses are classically attributed to the reactivation of long-lived, antigen-specific T lymphocytes that persist in a quiescent state. Determining mechanisms for the generation of memory T cells and dissecting the functional nature of the memory T cell pool has been encumbered by an inability to distinguish recently activated effector T cells from memory T cells. We have established new activation and biochemical criteria that distinguish effector and memory T cells and have applied these criteria to follow memory generation from activated cells in vivo. We found that the resultant memory T cell pool is heterogeneous and consists of effector-like and resting memory-like subsets that differ in expression of the homing receptor, CD62L. We discuss these findings in the context of memory T cell heterogeneity identified in human and mouse systems. These results suggest that more than one type of previously activated T cell can mediate recall or memory immune responses and that elucidating the fundamental phenotypic and functional features of memory T cell subsets is therefore critical to deciphering the complex nature of the memory immune response.

Animals↗

PubMedDate not supplied

IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells.

Lymphopenia is a serious consequence of HIV infection and the administration of cancer chemotherapeutic agents. Although growth factors can be administered to patients to increase circulating neutrophils, there is no effective method to stimulate CD8+ lymphocyte production in humans, in vivo. This report is the first to describe the administration of recombinant interleukin-7 to humans and demonstrates the ability of this cytokine to mediate selective increases in CD4+ and CD8+ lymphocytes along with a decrease in the percentage of CD4+ T-regulatory cells. These studies suggest an important role for interleukin-7 in the treatment of patients with lymphopenia.

Adult↗