Biomedical subjects

Sandhya Subramanian

Publications and source records attributed to Sandhya Subramanian.

At least 19 recordsLinked to original sources

PubMed2006

Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages.

Induction of stroke not only produces local ischemia and brain damage, but also has profound effects on peripheral immune responses. In the current study, we evaluated effects on spleen and blood cells 4 days after stroke induction. Surprisingly, there was a less inflammatory cytokine profile in the middle cerebral artery occlusion-affected right brain hemisphere at 96 h compared with earlier time points. Moreover, our results demonstrate that stroke leads to splenic atrophy characterized by a reduction in organ size, a drastic loss of splenocyte numbers, and induction of annexin V+ and TUNEL+ cells within the spleen that are in the late stages of apoptosis. The consequence of this process was to reduce T cell proliferation responses and secretion of inflammatory cytokines, resulting in a state of profound immunosuppression. These changes produced a drastic reduction in B cell numbers in spleen and blood, and a novel increase in CD4+FoxP3+ regulatory T cells. Moreover, we detected a striking increase in the percentage of nonapoptotic CD11b+ VLA-4-negative macrophages/monocytes in blood. Immunosuppression in response to brain injury may account for the reduction of inflammatory factors in the stroke-affected brain, but also potentially could curtail protective immune responses in the periphery. These findings provide new evidence to support the contention that damage to the brain caused by cerebral ischemia provides a powerful negative signal to the peripheral immune system that ultimately induces a drastic state of immunosuppression caused by cell death as well as an increased presence of CD4+FoxP3+ regulatory T cells.

Animals↗

PubMed2006

The DNA sequence, annotation and analysis of human chromosome 3.

After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.

Animals↗

PubMed2006

Experimental stroke induces massive, rapid activation of the peripheral immune system.

Clinical experimental stroke induces injurious local brain inflammation. However, effects on the peripheral immune system have not been well characterized. We quantified mRNA and protein levels for cytokines, chemokines, and chemokine receptors (CCR) in brain, spinal cord, peripheral lymphoid organs (spleen, lymph node, blood, and cultured mononuclear cells from these sources), and blood plasma after reversible middle cerebral artery occlusion (MCAO) or sham treatment in male C57BL/6 mice. Middle cerebral artery occlusion induced a complex, but organ specific, pattern of inflammatory factors in the periphery. At both 6 and 22 h after MCAO, activated spleen cells from stroke-injured mice secreted significantly enhanced levels of TNF-alpha, IFN-gamma, IL-6, MCP-1, and IL-2. Unstimulated splenocytes expressed increased chemokines and CCR, including MIP-2 and CCR2, CCR7 and CCR8 at 6 h; and MIP-2, IP-10, and CCR1 and CCR2 at 22 h. Also at 22 h, T cells from blood and lymph nodes secreted increased levels of inflammatory cytokines after activation. As expected, there were striking proinflammatory changes in postischemic brain. In contrast, spinal cord displayed suppression of all mediators, suggesting a compensatory response to intracranial events. These data show for the first time that focal cerebral ischemia results in dynamic and widespread activation of inflammatory cytokines, chemokines, and CCR in the peripheral immune system.

Animals↗

PubMed2005

Targeted, haplotype-resolved resequencing of long segments of the human genome.

Currently, challenges exist to acquire long-range (hundreds of kilobase pairs) phase-discriminated sequence across substantial numbers of individuals. We have developed a straightforward method for isolating and characterizing specific genomic regions in a haplospecific manner. Real-time PCR is carried out to STS content map and genotype pools of fosmid clones arrayed in 384-well microtiter plates. Single-nucleotide polymorphisms, microsatellite markers, and insertion-deletion polymorphisms are used to differentiate the target region into haplotype-specific tiling paths. DNA of clones from these tiling paths is retrieved from the library and either sequenced by standard shotgun methods or amplified in vitro and sequenced by a primer-based, directed method. This approach provides convenient access to complete, haplotype-resolved resequencing data from multiple individuals across tens to hundreds of thousands of basepairs. We illustrate its implementation with a detailed example of more than 400 kbp from the human CFTR region, across 15 individuals, and summarize our experience applying it to many other human loci.

Base Sequence↗

PubMed2005

Treatment of passive experimental autoimmune encephalomyelitis in SJL mice with a recombinant TCR ligand induces IL-13 and prevents axonal injury.

The major goal of this study was to evaluate the efficacy and mechanism of a rTCR ligand (RTL) construct (I-A(s)/proteolipid protein (PLP)-139-151 peptide = RTL401) for treatment of SJL/J mice developing passive experimental autoimmune encephalomyelitis (EAE) that did not involve coimmunization with the highly inflammatory CFA. Our results demonstrated clearly that RTL401 was highly effective in treating passive EAE, with kinetics of recovery from disease very similar to treatment of actively induced EAE. The potent RTL401 treatment effect was reflected by a partial reduction of infiltrating mononuclear cells into CNS, minimal inflammatory lesions in spinal cord, and preservation of axons injured in vehicle-treated mice during the progression of EAE. Interestingly, in the absence of CFA, RTL401 treatment strongly enhanced production of the Th2 cytokine, IL-13, in spleen, blood, and spinal cord tissue, with variable effects on other Th1 and Th2 cytokines, and no significant effect on the Th3 cytokine, TGF-beta1, or on FoxP3 that is expressed by regulatory T cells. Moreover, pretreatment of PLP-139-151-specific T cells with RTL401 in vitro induced high levels of secreted IL-13, with lesser induction of other pro- and anti-inflammatory cytokines. Given the importance of IL-13 for protection against EAE, these data strongly implicate IL-13 as a dominant regulatory cytokine induced by RTL therapy. Pronounced IL-13 levels coupled with marked reduction in IL-6 levels secreted by PLP-specific T cells from blood after treatment of mice with RTL401 indicate that IL-13 and IL-6 may be useful markers for following effects of RTL therapy in future clinical trials in multiple sclerosis.

Animals↗

PubMed2005

Ethinyl estradiol treats collagen-induced arthritis in DBA/1LacJ mice by inhibiting the production of TNF-alpha and IL-1beta.

We previously demonstrated the therapeutic effects of ethinyl estradiol (EE), an orally active estrogen and a component of birth control pills, in encephalitogenic autoimmune encephalomyelitis (EAE). In this study, we report the effectiveness of EE in treating collagen-induced arthritis (CIA) induced with bovine type II collagen (bCII) in DBA/1LacJ mice, a CIA susceptible strain. Both low and high doses of EE notably suppressed clinical and histological signs of CIA in a dose-dependent manner compared to vehicle-treated controls. Oral treatment with EE decreased proliferation and secretion of pro-inflammatory factors, TNF-alpha IFN-gamma, MCP-1 and IL-6 by bCII peptide-specific T cells, production of bCII-specific IgG2a antibodies, and mRNA for cytokines, chemokines and chemokine receptors in joint tissue. This is the first report demonstrating effective treatment of joint inflammation and clinical signs of CIA with orally administered ethinyl estradiol, thus supporting its possible clinical use for treating rheumatoid arthritis in humans.

Animals↗

PubMed2005

Ancient haplotypes of the HLA Class II region.

Allelic variation in codons that specify amino acids that line the peptide-binding pockets of HLA's Class II antigen-presenting proteins is superimposed on strikingly few deeply diverged haplotypes. These haplotypes appear to have been evolving almost independently for tens of millions of years. By complete resequencing of 20 haplotypes across the approximately 100-kbp region that spans the HLA-DQA1, -DQB1, and -DRB1 genes, we provide a detailed view of the way in which the genome structure at this locus has been shaped by the interplay of selection, gene-gene interaction, and recombination.

Alleles↗

PubMed2004

Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment.

CD4(+)CD25(+) regulatory T cells are crucial to the maintenance of tolerance in normal individuals. However, the factors regulating this cell population and its function are largely unknown. Estrogen has been shown to protect against the development of autoimmune disease, yet the mechanism is not known. We demonstrate that estrogen (17-beta-estradiol, E2) is capable of augmenting FoxP3 expression in vitro and in vivo. Treatment of naive mice with E2 increased both CD25(+) cell number and FoxP3 expression level. Further, the ability of E2 to protect against autoimmune disease (experimental autoimmune encephalomyelitis) correlated with its ability to up-regulate FoxP3, as both were reduced in estrogen receptor alpha-deficient animals. Finally, E2 treatment and pregnancy induced FoxP3 protein expression to a similar degree, suggesting that high estrogen levels during pregnancy may help to maintain fetal tolerance. In summary, our data suggest E2 promotes tolerance by expanding the regulatory T cell compartment.

Animals↗

PubMed2004

Monomeric recombinant TCR ligand reduces relapse rate and severity of experimental autoimmune encephalomyelitis in SJL/J mice through cytokine switch.

Our previous studies demonstrated that oligomeric recombinant TCR ligands (RTL) can treat clinical signs of experimental autoimmune encephalomyelitis (EAE) and induce long-term T cell tolerance against encephalitogenic peptides. In the current study, we produced a monomeric I-A(s)/PLP 139-151 peptide construct (RTL401) suitable for use in SJL/J mice that develop relapsing disease after injection of PLP 139-151 peptide in CFA. RTL401 given i.v. or s.c. but not empty RTL400 or free PLP 139-151 peptide prevented relapses and significantly reduced clinical severity of EAE induced by PLP 139-151 peptide in SJL/J or (C57BL/6 x SJL)F(1) mice, but did not inhibit EAE induced by PLP 178-191 or MBP 84-104 peptides in SJL/J mice, or MOG 35-55 peptide in (C57BL/6 x SJL/J)F(1) mice. RTL treatment of EAE caused stable or enhanced T cell proliferation and secretion of IL-10 in the periphery, but reduced secretion of inflammatory cytokines and chemokines. In CNS, there was a modest reduction of inflammatory cells, reduced expression of very late activation Ag-4, lymphocyte function-associated Ag-1, and inflammatory cytokines, chemokines, and chemokine receptors, but enhanced expression of Th2-related factors, IL-10, TGF-beta3, and CCR3. These results suggest that monomeric RTL therapy induces a cytokine switch that curbs the encephalitogenic potential of PLP 139-151-specific T cells without fully preventing their entry into CNS, wherein they reduce the severity of inflammation. This mechanism differs from that observed using oligomeric RTL therapy in other EAE models. These results strongly support the clinical application of this novel class of peptide/MHC class II constructs in patients with multiple sclerosis who have focused T cell responses to known encephalitogenic myelin peptides.

Amino Acid Sequence↗

PubMed2004

CD4 T-cell epitopes of human alpha B-crystallin.

Of potential importance to multiple sclerosis (MS), oligodendroglial alpha B-crystallin is expressed and associated with the myelin sheath at the earliest stage of MS lesion development. We selected T-cell lines specific for human alpha B-crystallin from peripheral blood mononuclear cells (PBMC) of HLA-DR2 homozygous MS patients and found that the alpha B-crystallin-specific T-cells were CD4+ and restricted by DRB1*1501, and expressed Th1 cytokines. The CD4 T-cell epitopes of human alpha B-crystallin were determined by proliferation of alpha B-crystallin-specific T-cell lines to 17 20-mer synthetic overlapping peptides spanning the entire molecule of human alpha B-crystallin. It was found that the HLA-DR2 donor-derived alpha B-crystallin-specific T-cell lines proliferated to alpha B-crystallin peptides 21-40, 41-60, and to a lesser extent, 131-150. These T-cell proliferation responses were associated with intracellular expression of interleukin-2 (IL-2) and secretion of interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha). The amino acid sequences of these peptides were compatible with predicted HLA-DR2-restricted binding motifs. PBMC of an early active MS patient proliferated to the epitope-containing peptides significantly better than did those of later stage MS patients or healthy controls. Taken together, these findings suggest that autoreactive alpha B-crystallin-specific Th1 cells may have the potential to contribute to MS pathogenesis.

Amino Acid Sequence↗

PubMed2004

A synthetic androstene analogue inhibits collagen-induced arthritis in the mouse.

Dehydroepiandrosterone (DHEA), a precursor of immune-regulating hormones (IRH) including the androstenes, has attracted much interest over the last several decades because of its many antiaging, metabolic, and immune modulating effects. 5-Androstene-16alpha fluoro-17-one (fluasterone, also known as HE2500) is a synthetic androstene analogue that retains anti-inflammatory, antiproliferative, and immune-regulating activities of the parent molecule, but is nontoxic and practically devoid of androgenic or estrogenic side effects. In the present studies, we tested the ability of fluasterone to limit disease in the DBA mouse model of collagen-induced arthritis (CIA). We found that mice receiving injections of fluasterone displayed significant delay in onset, decrease in CIA peak score, and significant decrease of the daily mean clinical score. Benefit was associated with significant decreases in (1). bovine type II collagen (bCII)-specific IgG(1) and IgG(2a) antibody levels in serum; (2). production of TNF-alpha, IL-6, IFN-gamma, but not IL-10; (3). lymphocyte proliferative response to bCII protein; and (4). joint inflammation, erosion, and synovial proliferation as judged by histological analysis. This is the first study to report that an IRH can ameliorate ongoing disease in a CIA mouse model with relevance to RA and to correlate that finding with decreases in pro-inflammatory cytokines.

Animals↗

PubMed2004

T lymphocytes do not directly mediate the protective effect of estrogen on experimental autoimmune encephalomyelitis.

Gender influences mediated by 17 beta-estradiol (E2) have been associated with susceptibility to and severity of autoimmune diseases such as diabetes, arthritis, and multiple sclerosis. In this regard, we have shown that estrogen receptor-alpha (Esr1) is crucial for the protective effect of 17 beta-estradiol (E2) in murine experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis. The expression of estrogen receptors among various immune cells (eg, T and B lymphocytes, antigen-presenting cells) suggests that the therapeutic effect of E2 is likely mediated directly through specific receptor binding. However, the target immune cell populations responsive to E2 treatment have not been identified. In the current study, we induced EAE in T-cell-deficient, severe combined immunodeficient mice or in immunocompetent mice with encephalitogenic T cells from wild-type Esr1+/+ or Esr1 knockout (Esr1-/-) donors and compared the protective E2 responses. The results showed that E2-responsive, Esr1+/+ disease-inducing encephalitogenic T cells were neither necessary nor sufficient for E2-mediated protection from EAE. Instead, the therapeutic response appeared to be mediated through direct effects on nonlymphocytic, E2-responsive cells and down-regulation of the inflammatory response in the central nervous system. These results provide the first demonstration that the protective effect of E2 on EAE is not mediated directly through E2-responsive T cells and raise the alternative possibility that nonlymphocytic cells such as macrophages, dendritic cells, or other nonlymphocytic cells are primarily responsive to E2 treatment in EAE.

Animals↗

PubMed2004

Estrogen receptor-1 (Esr1) and -2 (Esr2) regulate the severity of clinical experimental allergic encephalomyelitis in male mice.

Estrogens and estrogen-receptor signaling function in establishing and regulating the female immune system and it is becoming increasingly evident that they may play a similar role in males. We report that B10.PL/SnJ male mice with a disrupted estrogen receptor-1 (alpha) gene (Esr1(-/-)) develop less severe clinical experimental allergic encephalomyelitis (EAE) compared to either Esr1(+/-) or wild-type (Esr1(+/+)) controls when immunized with myelin basic protein peptide Ac1-11 (MBP(Ac1-11)). In contrast, the disease course in B10.PL/SnJ male mice with a disrupted estrogen receptor-2 (beta) gene (Esr2(-/-)) does not differ from that of wild-type (Esr2(+/+)) mice. However, Esr2(+/-) mice do develop more severe clinical disease with an earlier onset indicating that heterosis at Esr2 plays a significant role in regulating EAE in males. No significant differences in central nervous system histopathology or MBP(Ac1-11)-specific T-cell responses as assessed by proliferation and interleukin-2 production were observed as a function of either Esr1 or Esr2 genotype. An analysis of cytokine/chemokine secretion by MBP(Ac1-11)-specific T cells revealed unique Esr1 and Esr2 genotype-dependent regulation. Interferon-gamma secretion was found to be negatively regulated by Esr1 whereas interleukin-6 and tumor necrosis factor-alpha secretion exhibited classical Esr2 gene dose responses. Interestingly, MCP-1 displayed distinctively unique patterns of genotype-dependent regulation by Esr1 and Esr2. The contribution of the hematopoietic and nonhematopoietic cellular compartments associated with the heterotic effect at Esr2 in regulating the severity of clinical EAE was identified using reciprocal hematopoietic radiation bone marrow chimeras generated between male wild-type and Esr2(+/-) mice. Wild-type --> Esr2(+/-) mice exhibited EAE equivalent in severity to that seen in Esr2(+/-) --> Esr2(+/-) control constructs; both of which were more severe than the clinical signs observed in Esr2(+/-) --> wild-type and wild-type --> wild-type mice. These results indicate that the heterotic effect at Esr2 is a function of the nonhematopoietic compartment.

Animals↗

PubMed2003

Estradiol treatment redirects the isotype of the autoantibody response and prevents the development of autoimmune arthritis.

A number of clinical and experimental observations have been made relating elevated estrogen levels with the amelioration of autoimmune diseases, yet questions remain about the levels required for efficacy as well as the mechanism of disease inhibition. Using the collagen-induced arthritis (CIA) model, we have studied the effects of physiological, sustained levels of 17beta-estradiol in preventing the development of autoimmune arthritis and analyzed the changes in the autoimmune response. Using time-release pellets of 17beta-estradiol, arthritis development was significantly inhibited in three different strains of CIA-susceptible mice compared with the effect of placebo treatment, and serum estradiol levels similar to those of mice in estrus were found to be equally effective as higher estradiol concentrations. Analysis of the autoimmune response in the estradiol-treated mice indicated that T cell production of IFN-gamma was markedly decreased, and significant decreases were also observed in levels of IL-10 and GM-CSF produced by lymph nodes cells from estradiol-treated mice. Although the total IgG anti-CII response was only minimally affected by estrogen treatment, a significant reduction in the levels of IgG2a anti-CII Abs and an increase in the levels of IgG1 anti-CII Abs were observed in estradiol-treated mice. These data indicate that estradiol treatment altered the Th profile of the autoimmune T cell response, which, in turn, altered the production of IgG Abs to an isotype that is poor at fixing complement, an important component in the immunopathogenesis of CIA.

Animals↗

PubMed2003

CNS gene expression pattern associated with spontaneous experimental autoimmune encephalomyelitis.

Transgenic mice with T-cell receptor (TCR) specific for myelin basic protein (MBP)-Ac1-11 peptide and homozygous for the RAG-1 mutation (T/R- mice) spontaneously develop acute progressive experimental autoimmune encephalomyelitis (Sp-EAE) mediated by CD4+ T cells. Microarray analysis of spinal cord tissue obtained from symptomatic versus non-symptomatic T/R- mice revealed strongly upregulated transcripts for genes involved in antigen presentation and processing, signal transduction, transcription regulation, metabolism, development, cell cycle, and many other processes involved in the induction of clinical and pathological signs of Sp-EAE. Several highly expressed genes were related directly to inflammation, including cytokines/receptors, chemokines/receptors, acute phase, complement molecules, and others. Many CNS-specific genes were also upregulated in sick mice. Abundance of message for the Tg TCR BV8S2 gene as well as several monocyte/macrophage-associated genes would suggest that both components play a crucial role in the pathogenesis of Sp-EAE. The profile of transcriptional changes found during the development of Sp-EAE provides the first description of the encephalitogenic process in the absence of purposeful immunization with myelin peptides and immune-enhancing adjuvants. This unique approach is the first to implicate molecules and pathways that contribute naturally to onset of paralysis and demyelination, and thus may provide unique insights and novel treatment strategies for human diseases such as multiple sclerosis.

Animals↗

PubMed2003

Transfer of severe experimental autoimmune encephalomyelitis by IL-12- and IL-18-potentiated T cells is estrogen sensitive.

The aim of this study was to evaluate the roles of IL-18 and IL-12 in potentiating the encephalitogenic activity of T cell lines specific for myelin oligodendrocyte glycoprotein (MOG(35-55)). MOG-specific T cells stimulated with anti-CD3 and anti-CD28 in the presence of IL-12 or IL-18 alone transferred only mild experimental autoimmune encephalomyelitis (EAE) into a low percentage of recipients. However, T cells cocultured with both cytokines transferred aggressive clinical and histological EAE into all recipients. Coculture of T cells with IL-12 enhanced the secretion of IFN-gamma, but not TNF-alpha, whereas coculture with IL-18 enhanced the secretion of TNF-alpha, but not INF-gamma. However, coculture with both IL-18 and IL-12 induced high levels of both TNF-alpha and IFN-gamma. Additionally, IL-12 selectively enhanced mRNA expression of CCR5, whereas IL-18 selectively enhanced the expression of CCR4 and CCR7, and CCR4 and CCR5 were coexpressed on the surface of T cells cocultured with IL-12 and IL-18. Finally, estrogen treatment, previously found to inhibit both TNF-alpha and IFN-gamma production, completely abrogated all signs of passive EAE. These data demonstrate that optimal potentiation of encephalitogenic activity can be achieved by conditioning MOG-specific T cells with the combination of IL-12 and IL-18, which, respectively, induce the secretion of IFN-gamma/CCR5 and TNF-alpha/CCR4/CCR7, and that estrogen treatment, which is known to inhibit both proinflammatory cytokines, can completely ablate this aggressive form of passive EAE.

Adjuvants, Immunologic↗

PubMed2003

Oral feeding with ethinyl estradiol suppresses and treats experimental autoimmune encephalomyelitis in SJL mice and inhibits the recruitment of inflammatory cells into the central nervous system.

There is much interest in the possible ameliorating effects of estrogen on various autoimmune diseases. We previously established the protective effects of 17 beta-estradiol (E2) on experimental autoimmune encephalomyelitis (EAE). In the current study we investigated the effectiveness of oral treatment with ethinyl estradiol (EE) on EAE and the mechanisms involved. Ethinyl estradiol is a semisynthetic estrogen compound found in birth control pills, and its chemical structure allows this compound to retain activity when given orally. We found that oral EE, like E2, drastically suppressed EAE induced by proteolipid protein 139-151 peptide when given at initiation of EAE. However, unlike E2, EE reduced clinical severity when given after the onset of clinical signs. Treatment with EE significantly decreased the secretion of proinflammatory cytokines (IFN-gamma, TNF-alpha, and IL-6) by activated T cells as well as the expression of a key matrix metalloproteinase, disease-mediating chemokines/receptors, and IgG2a levels, but increased the expression of TGF-beta 3 in the CNS. The absence of infiltrating lymphocytes together with the suppression of cytokines, matrix metalloproteinase, and chemokines/receptors suggests that EE, like E2, protects mice from EAE by inhibiting the recruitment of T cells and macrophages into the CNS. These results suggest that oral ethinyl estradiol might be a successful candidate as therapy for multiple sclerosis.

Administration, Oral↗

PubMed2003

Endogenous CD4+BV8S2- T cells from TG BV8S2+ donors confer complete protection against spontaneous experimental encephalomyelitis (Sp-EAE) in TCR transgenic, RAG-/- mice.

To investigate regulatory mechanisms which naturally prevent autoimmune diseases, we adopted the genetically restricted immunodeficient (RAG-1(-/-)) myelin basic protein (MBP)-specific T cell receptor (TCR) double transgenic (T/R-) mouse model of spontaneous experimental autoimmune encephalomyelitis (Sp-EAE). Sp-EAE can be prevented after transfer of CD4+splenocytes from naïve immunocompetent mice. RAG-1+ double transgenic (T/R+) mice do not develop Sp-EAE due to the presence of a very small population (about 2%) of non-Tg TCR specificities. In this study, CD4+BV8S2+ T cells that predominate in T/R+ mice, and three additional populations, CD4+BV8S2-, CD4-CD8-BV8S2+, and CD4-CD8+BV8S2+ T cells that expanded in T/R+ mice after immunization with MBP-Ac1-11 peptide, were studied for their ability to prevent Sp-EAE in T/R- mice. Only the CD4+BV8S2- T cell population conferred complete protection against Sp-EAE, similar to unfractionated splenocytes from non-Tg donors, whereas CD4-CD8-BV8S2+ and CD4+BV8S2+ T cells conferred partial protection. In contrast, CD4-CD8+BV8S2+ T cells had no significant protective effects. The highly protective CD4+BV8S2- subpopulation was CD25+, contained non-clonotypic T cells, and uniquely expressed the CCR4 chemokine receptor. Protected recipient T/R- mice had marked increases in CD4+CD25+ Treg-like cells, retention of the pathogenic T cell phenotype in the spleen, and markedly reduced inflammation in CNS tissue. Partially protective CD4+BV8S2+ and CD4- CD8-BV8S2+ subpopulations appeared to be mainly clonotypic T cells with altered functional properties. These three Sp-EAE protective T cell subpopulations possessed distinctive properties and induced a variety of effects in T/R- recipients, thus implicating differing mechanisms of protection.

Animals↗