Major histocompatibility complex proteins and TCRs: do they really go together like a horse and carriage?
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Allergy and Immunology↗
Biomedical subjects
P Marrack
Publications and source records attributed to P Marrack.
The growth of the very large CD8+ T cell clones in older mice is controlled by cytokines.
Older humans and mice frequently contain very large clones of CD8(+) T cells. In mice these cells are phenotypically very similar to memory CD8(+) T cells. Like memory CD8(+) T cells, most members of the clones are in continuous slow division, apparently independently of Ag stimulation. Proliferation of the CD8(+) clonal T cells is inhibited in mice treated with Ab to the IL-2R beta-chain that blocks signaling by either IL-2 or IL-15. However, inhibition of IL-2 increases the numbers of dividing clonal cells. Therefore, like normal memory CD8(+) T cells, expansion of the clones is driven by IL-15 and inhibited by IL-2 and is probably limited by the amounts of IL-15 and IL-2 present in the host. Control by these two cytokines may account for the fact that, although the clones can be very large, they do not overwhelm or kill their hosts. Nevertheless the clonal cells compete successfully with normal memory CD8(+) T cells for growth. Perhaps the clonal cells use IL-15 more effectively or are more resistant to the inhibitory effects of IL-2. Thus they might affect the immune response of their hosts by competing for factors that stimulate and inhibit normal CD8(+) memory T cells.
Aging↗
Mutations changing the kinetics of class II MHC peptide exchange.
IE/DR MHC class II molecules have an extensive H-bonding network under the bound peptide. In IE(k), two alpha chain acidic amino acids in the core of this network were mutated to amides. At low pH, the mutant molecule exchanged peptide much more rapidly than the wild-type. The crystal structure of the mutant IE(k) revealed the loss of a single buried water molecule and a reorganization of the predicted H-bonding network. We suggest that these mutations enhance the transition of MHC class II to an open conformation at low pH allowing the bound peptide to escape. In wild-type IE(k), the need to protonate these amino acids also may be a bottleneck in the return to a closed conformation after peptide binding.
Amino Acid Sequence↗
Immunological adjuvants promote activated T cell survival via induction of Bcl-3.
Injection of soluble protein antigen into animals causes abortive proliferation of the responding T cells. Immunological adjuvants boost T cell responses at least in part by increasing the survival of activated T cells during and after the initial proliferative phase of their clonal expansion. To understand how adjuvants promote T cell survival, we used gene microarrays to analyze gene expression in T cells activated either with antigen alone or in the presence of two different adjuvants. Among the genes whose expression was increased by both adjuvants was the IkappaB family member Bcl-3. Retroviral infection experiments showed that expression of Bcl-3 increased survival of activated T cells in vitro and in vivo. Adjuvants may therefore improve survival of activated T cells via induction of Bcl-3.
Adjuvants, Immunologic↗
Autoimmune disease: why and where it occurs.
Autoimmune disease is controlled by genetic and environmental factors. Both of these affect susceptibility to autoimmunity at three levels: the overall reactivity of the immune system, the specific antigen and its presentation, and the target issue.
Antigens↗
T cells compete for access to antigen-bearing antigen-presenting cells.
These studies tested whether antigenic competition between T cells occurs. We generated CD8(+) T cell responses in H-2(b) mice against the dominant ovalbumin epitope SIINFEKL (ova8) and subdominant epitope KRVVFDKL, using either vaccinia virus expressing ovalbumin (VV-ova) or peptide-pulsed dendritic cells. CD8(+) T cell responses were visualized by major histocompatibility complex class I-peptide tetrameric molecules. Transfer of transgenic T cells with high affinity for ova8 (OT1 T cells) completely inhibited the response of host antigen-specific T cells to either antigen, demonstrating that T cells can directly compete with each other for response to antigen. OT1 cells also inhibited CD8(+) T cell responses to an unrelated peptide, SIYRYGGL, providing it was presented on the same dendritic cells as ova8. These inhibitions were not due to a more rapid clearance of virus or antigen-presenting cells (APCs) by the OT1 cells. Rather, the inhibition was caused by competition for antigen and antigen-bearing cells, since it could be overcome by the injection of large numbers of antigen-pulsed dendritic cells. These results imply that common properties of T cell responses, such as epitope dominance and secondary response affinity maturation, are the result of competitive interactions between antigen-bearing APC and T cell subsets.
Amino Acid Sequence↗
Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers.
We characterized antigen-specific CD4(+) T cells in six patients with treatment-resistant Lyme arthritis, using an HLA-DRB1*0401 major histocompatibility complex (MHC) class II tetramer covalently loaded with OspA(164-175), an immunodominant epitope of Borrelia burgdorferi. Direct analysis of OspA-tetramer binding CD4(+) cells in patients expressing the HLA-DRB1*0401 allele revealed frequencies of between <0.005 and 0.1% in peripheral blood (n = 6), and between <0.005 and 3.1% in synovial fluid (n = 3). OspA-tetramer(+)CD4(+) cells were directly cloned at 1 cell per well and expanded by mitogen and IL-2 on allogeneic feeder cells. As measured by [(3)H]thymidine incorporation, 95% of 168 T cell clones from synovial fluid binding the OspA-tetramer were antigen-reactive. Clones generated from peripheral blood revealed a different pattern of responsiveness when compared with clones generated from synovial fluid, as measured by proliferation, IFN-gamma, and IL-13 secretion. These clones, selected on the basis of their peptide binding, also responded to whole protein, but with a different cytokine profile. Our studies demonstrate that MHC class II tetramers can be used in humans to directly identify, isolate, and characterize antigen-reactive T cells from an inflammatory compartment.
Antigens, Surface↗
Control of homeostasis of CD8+ memory T cells by opposing cytokines.
Memory T cells maintain their numbers for long periods after antigen exposure. Here we show that CD8+ T cells of memory phenotype divide slowly in animals. This division requires interleukin-15 and is markedly increased by inhibition of interleukin-2 (IL-2). Therefore, the numbers of CD8+ memory T cells in animals are controlled by a balance between IL-15 and IL-2.
Animals↗
Activation-induced inhibition of interleukin 6-mediated T cell survival and signal transducer and activator of transcription 1 signaling.
The cytokines interleukin (IL)-2, IL-4, IL-6, IL-7, and IL-15 have all previously been shown to inhibit resting T cell death in vitro. We have found a difference in the response of T cells to IL-6, depending on the activation status of the cells. IL-6 inhibited the death of naive T cells, but had no effect on the death of either superantigen-activated T cells, or T cells bearing memory markers. This was true even when the resting and activated T cells were isolated from the same animal; thus, the determining factor for IL-6 insensitivity was the activation status or activation history of the cell, and not the milieu in the animal from which the cells were isolated. Activated T cells expressed lower levels of IL-6 receptors on their surfaces, yet there were sufficient levels of receptors for signaling, as we observed similar levels of signal transducer and activator of transcription (Stat)3 phosphorylation in resting and activated T cells treated with IL-6. However, there was profound inhibition of IL-6-induced Stat1 phosphorylation in activated T cells compared with resting T cells. These data suggest that there is activation-induced inhibition of IL-6 receptor signaling in T cells. This inhibition appears to be specific for some but not all of the IL-6-mediated signaling cascades in these cells.
Animals↗
Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis.
Considerable evidence indicates that CD4(+) T cells are important in the pathogenesis of rheumatoid arthritis (RA), but the antigens recognized by these T cells in the joints of patients remain unclear. Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are among the most likely synovial antigens to be involved in T cell stimulation in RA. Furthermore, experiments have defined dominant peptide determinants of these antigens when presented by HLA-DR4, the most important RA-associated HLA type. We used fluorescent, soluble peptide-DR4 complexes (tetramers) to detect synovial CD4(+) T cells reactive with CII and HCgp39 in DR4(+) patients. The CII-DR4 complex bound in a specific manner to CII peptide-reactive T cell hybridomas, but did not stain a detectable fraction of synovial CD4(+) cells. A background percentage of positive cells (<0.2%) was not greater in DR4 (DRB1*0401) patients compared with those without this disease-associated allele. Similar results were obtained with the gp39-DR4 complex for nearly all RA patients. In a small subset of DR4(+) patients, however, the percentage of synovial CD4(+) cells binding this complex was above background and could not be attributed to nonspecific binding. These studies demonstrate the potential for peptide-MHC class II tetramers to be used to track antigen-specific T cells in human autoimmune diseases. Together, the results also suggest that the major oligoclonal CD4(+) T cell expansions present in RA joints are not specific for the dominant CII and HCgp39 determinants.
Adult↗
Genomic-scale analysis of gene expression in resting and activated T cells.
Recent advances in gene array technology and isolation of lymphocytes now allow comprehensive analysis of gene expression in many different types of T cells. So far only a few sets of results have been published. However it is already clear that these analyses provide accurate measurements of gene expression in T cells. This technology offers the first opportunity to examine global and subtle changes in gene expression in response to specific stimuli.
Animals↗
Homeostasis of alpha beta TCR+ T cells.
Cytokines contribute to T cell homeostasis at all stages of T cell existence. However, the particular cytokine involved varies as T cells progress from a naïve through an activated to a memory state. In many cases the important cytokines are members of the interleukin 2 subfamily of the short-chain type I cytokines. A case is made for the idea that the evolutionary divergence of the short-chain family allowed for concurrent divergence in leukocytes.
Animals↗
Production and characterization of T cell hybridomas.
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Animals↗
Activation changes the spectrum but not the diversity of genes expressed by T cells.
During activation T cells are thought to change their patterns of gene expression dramatically. To find out whether this is true for T cells activated in animals, the patterns of genes expressed in resting T cells and T cells 8 and 48 hr after activation were examined by using Affymetrix gene arrays. Gene arrays gave accurate comparisons of gene expression in the different cell types because the expression of genes known to vary during activation changed as expected. Of the approximately 6,300 genes assessed by the arrays, about one-third were expressed to appreciable extents in any of the T cells tested. Thus, resting T cells express a surprisingly large diversity of genes. The patterns of gene expression changed considerably within 8 hr of T cell activation but returned to a disposition more like that of resting T cells within 48 hr of exposure to antigen. Not unexpectedly, the activated T cells expressed genes associated with cell division at higher levels than resting T cells. The resting T cells expressed a number of cytokine receptor genes and some genes thought to suppress cell division, suggesting that the state of resting T cells is not a passive failure to respond to extant external stimuli.
Animals↗
An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro.
Multimeric peptide/class II MHC staining reagents were synthesized and shown to bind with appropriate specificity to T cell hybridomas. A small, expanded population of T cells detected with one of these reagents in peptide-immunized C57BL/10 mice persisted for several months. This population expanded further on secondary immunization. Equating the extent of binding of this reagent to T cell receptor affinity, we saw little correlation of immunizing peptide dose to T cell receptor affinity at the peak of the primary response. However, there was an inverse relation between peptide dose and the apparent receptor affinity of the T cells that were present several months after a primary response or after a secondary stimulation either in vivo or in vitro.
Animals↗
CD4+ T cell division in irradiated mice requires peptides distinct from those responsible for thymic selection.
We investigated the mechanism by which alpha/beta T cells expand upon transfer to T cell-deficient host mice by injecting carboxyfluorescein diacetate succinimidyl ester-labeled T cells into mice depleted of T cells by sublethal irradiation. We found that CD4+ T cells divided when transferred to irradiated hosts and that the division of more than half of these cells required class II expression. However, division of transferred CD4+ T cells did not occur in irradiated hosts that expressed class II molecules occupied solely by the peptide responsible for thymic selection, indicating that peptides distinct from those involved in thymic selection cause the division of CD4+ T cells in irradiated mice. These data establish that class II-bound peptides control the expansion of CD4+ T cells transferred to T cell-deficient hosts and suggest that the same peptides contribute to the maintenance of T cell numbers in normal mice.
Animals↗
Proposed changes for NIH's Center for Scientific Review. Panel on Scientific Boundaries for Review. Center for Scientific Review Advisory Committee, National Institutes of Health.
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National Institutes of Health (U.S.)↗
Bystander virus infection prolongs activated T cell survival.
In animals, T cells often die rapidly after activation, unless activation occurs in the presence of inflammatory factors. To understand how such activated cells survive to participate in immune responses, we studied the effects of viral infection on T cells responding to an unrelated superantigen. Normal T cells activated by superantigen in uninfected mice died as a result of their activation, whereas T cells that were activated during vaccinia infection survived longer in vivo and in culture. This bystander effect of viral infection on activated T cells was independent of effects on the magnitude of the initial T cell response, on induction of Bcl-2 and Bcl-x, on T cell proliferation, and on Fas killing. The failure of such effects to predict the fate of activated T cells in vivo indicates that virus infections shape T cell responses via mechanisms that differ from those described previously. These mechanisms may contribute to the ability of viral infections to induce autoimmunity.
Animals↗