Interactions between peripheral blood CD8 T lymphocytes and intestinal epithelial cells (iEC)

Intestinal intraepithelial lymphocytes (iIEL) are primarily CD8 cells and most of them have a CD28^? phenotype, the phenotype of effector cytotoxic T cells. We asked whether the predominance of CD8⁺ CD28^? T cells in the gut may result from peripheral blood T cells preferentially migrating to the iIEL compartment and adhering to iEC. Compared with CD4 cells, adhesion of resting CD8⁺ T cells to iEC cell lines was significantly higher. Adhesion could be blocked with a MoAb to gp180, a molecule expressed on iEC which is known to interact with CD8/lck. No significant difference in the level of adhesion was observed between CD8⁺ CD28⁺ and CD8⁺ CD28^? T cells. Thus CD8 cells may preferentially migrate to the iIEL compartment, but loss of CD28 expression could occur in situ after migration. Consistent with this hypothesis, the CD8⁺ CD28^? cells became enriched after co-culturing T cells with iEC cell lines and primary iEC. Induction of the CD8⁺ CD28^? phenotype in cord blood and adult T cells was observed in co-cultures with iEC and also with mitogens and superantigens. In the latter case, CD28 down-modulation was seen specifically in the Vβ subset targeted by the superantigen, indicating that loss of CD28 expression is a direct result of T cell receptor (TCR)-mediated stimulation. The combined results suggest that CD8⁺ CD28^? T cells are antigen experienced T cells, and that they may have a survival advantage in the presence of gut epithelial cells in vitro. This may contribute to the predominance of CD8⁺ CD28^? T cells in the iIEL compartment.     

Programme budgeting and marginal analysis: an approach to priority setting in need of refinement

Programme budgeting is enjoying a revival in the British National Health Service primarily because of its recent coupling with marginal analysis. As well as providing a means of mapping activity and expenditure from the institutions providing care to the population receiving it, programme budgeting and marginal analysis aim to assist strategic planning by indicating where net benefits might be increased by reallocating spending within programmes. However, the method to achieve this is not yet sufficiently refined and results to date have been mixed. In particular, the approach to identifying options for evaluation is flawed because of the importance attached to the role of 'expert' groups. A more systematic technique is suggested to overcome present methodological deficiencies.     

Staphylococcus aureus express unique superantigens depending on the tissue source

A comprehensive analysis of Staphylococcus aureus superantigen (SAG) genes was undertaken in isolates from a major hospital and compared with isolates from patients with toxic shock syndrome (TSS). Polymerase chain reaction (PCR) analysis included recently discovered SAGs. Staphylococcal enterotoxin (SE) G and SEI were uniquely expressed in genital isolates. Genital isolates were similar to TSS isolates, although the latter frequently expressed TSS toxin 1. Both had a high frequency of SEG/SEI and a high number of SAG genes per bacterium. Detection of an SAG gene by PCR correlated with positive results in functional assays for SAG activity. Levels of serum antibodies to SEG and SEI, but not to other superantigens, were higher in healthy women than in men and served as an independent measure of the higher frequency of exposure to SEG/SEI among women. Together, the data suggest a role for SEG/SEI or closely linked genes in the adaptation of S. aureus to the genital mucosa environment.     

Highly Biased CDR3 Usage in Restricted Sets of β Chain Variable Regions During Viral Superantigen 9 Response

Superantigens encoded by the mouse mammary tumor virus can stimulate a large proportion of T cells through interaction with germline-encoded regions of the T cell receptor β chain like the hypervariable region 4 (HV4) loop. However, several lines of evidence suggest that somatically generated determinants in the CDR3 region might influence superantigen responses. We stimulated T cells from donors differing at the BV6S7 allele with vSAG9 to assess the nature and structure of the T cell receptor in amplified T cells and to evaluate the contribution of non-HV4 elements in vSAG recognition. This report demonstrates that vSAG9 stimulation caused the expansion of TCR BV6-expressing T cells, although to varying degrees depending on the BV6 subfamily. The BV6S7 subfamily was preferentially expanded in all donors, but in donors homozygous for the BV6S7*2 allele, a significant number of BV6S5 T cells were amplified and showed a highly biased β chain junctional region (BJ) and CDR3 usage. As CDR3 regions are involved in major histocompatibility complex (MHC)–peptide interaction, such a selection is highly suggestive of an intimate MHC–TCR interaction and would imply that the topology of the MHC-vSAG-TCR complex is similar to the one occurring during conventional antigen recognition.     

Evaluation of the relative cost-effectiveness of treatments for infertility in the UK

This paper aims to complement existing clinical guidelines byproviding evidence of the relative cost-effectiveness of treatmentsfor infertility in the UK. A series of decision–analyticalmodels have been developed to reflect current diagnostic andtreatment pathways for the five main causes of infertility.Data to populate the models are derived from a systematic reviewand routine National Health Service activity data, and are augmentedwith expert opinion. Costs are derived from an analysis of extra-contractualreferral tariffs and private sector data. Sensitivity analysishas been carried out to take account of the uncertainty of modelparameters and to allow results to be interpreted in the lightof local circumstances. Results of the modelling exercise suggestin-vitro fertilization is the most cost-effective treatmentoption for severe tubal factors and endometriosis, with surgerythe most cost-effective in the case of mild or moderate disease.Ovulatory factors should be treated medically with the additionof laparoscopic ovarian diathermy in the presence of polycysticovarian syndrome. For other causes, stimulated intrauterineinsemination (unexplained and moderate male factor) and stimulateddonor intrauterine insemination (severe male) are cost-effective.     

Altered expression of CD4, CD54, CD62L, and CCR5 in primary lymphocytes productively infected with the human immunodeficiency virus

Infection of T cells with HIV-1 induces loss of CD4 and HLA class I from the cell surface. In the present article we have investigated whether changes in expression of other cell surface molecules could be related to HIV infection. To detect HIV-infected cells at the single-cell level, peripheral blood lymphocytes were infected in vitro with HIV-HSA, a reporter virus encoding the murine heat-stable antigen. Expression of HSA on activated primary lymphocytes was an efficient indicator of productive infection. Expression of the majority of the cell surface proteins studied was unaffected by HIV infection (HLA class I, II, CD11a, CD18, CD25, CD27, CD28, CD29, CD30, CD31, CD38, CD44, CD45R0, CD49d, CD57, CD94, CD95, and CXCR4). However, phenotypic changes specific to the productively infected cells were detected. Expression of the CD4 molecule was progressively lost and this was closely associated with loss of CD62L expression, a molecule involved in T cell homing into the lymph nodes. By contrast, T cells productively infected with this T-tropic reporter virus were enriched for CD54, and for CCR5, the main coreceptor for M-tropic viruses. Given the roles of CD62L, CD54, and CCR5 in lymphocyte trafficking, these results suggest that cells productively infected with HIV might have altered homing patterns in vivo.     

A hairy cell leukemia associated antigen (HC2) has a distinct role in normal B cell differentiation

Activation antigens expressed by activated B cells, but not by resting B cells, are excellent candidate molecules for lymphokine receptors, which are expressed after B cell activation. HC2 is a previously described hairy cell leukemia associated antigen, which is not expressed by chronic lymphocytic leukemia B cells. HC2 is also found on activated B cells but not on resting B cells. Here we demonstrate that HC2 is not a B lineage restricted antigen and may be expressed by other activated cell types. Antibody to HC2 inhibits the activity of partially purified B cell growth factor in two different assays and inhibits B cell differentiation induced by pokeweed mitogen or Staphylococcus aureus Cowan stain I with interleukin-2. The HC2 antigen may therefore have a distinct role in normal B cell differentiation.     

A new HLA-linked T cell membrane molecule, related to the beta chain of the clonotypic receptor, is associated with T3

The 38 kD molecule is noncovalently associated with beta 2 microglobulin (beta 2m)-free HLA heavy chain-like molecule, and thus forms a second heterodimer distinct from the clonotypic alpha/beta T cell receptor expressed by the same clone of leukemia cells. This second heterodimer (38 kD/HLA) is variably expressed and appears to be associated with the T3 molecule. We suggest, therefore, that it has a functional role in T cell activation.     

T cell receptor V-segment frequencies in peripheral blood T cells correlate with human leukocyte antigen type

We compared T cell receptor (TCR) V-segment frequencies in human leukocyte antigen (HLA) identical siblings to sibling pairs who differ at one or both HLA haplotypes using four V beta-specific and one V alpha-specific monoclonal antibody. In every one of nine families HLA-identical sibs had the most similar patterns of V-segment frequencies in their peripheral blood, whereas totally mismatched sibs were, in general, the most dissimilar; HLA haploidentical sibs tended to be intermediate between the two groups. The degree of similarity among HLA-identical sibs was comparable to that observed among three pairs of identical twins suggesting that HLA is the major genetic component influencing TCR V-segment frequency. Consistent with this observation, it was found that the frequency of T cells expressing particular V beta segments was skewed towards either CD4+ or CD8+ cells indicating that T cells expressing some V beta genes may be positively selected primarily by class I or class II major histocompatibility complex proteins. Finally, it was observed that individuals who express the HLA class I specificity, B38, tend to express high levels of V alpha 2.3+ cells among their CD8+ T cells. These observations represent definitive proof that human V-segment frequencies are profoundly influenced by the HLA complex.     

T cell antigen receptor V gene usage. Increases in V beta 8+ T cells in Crohn''s disease.

Crohn's disease represents part of a spectrum of inflammatory bowel diseases characterized by immune regulatory defects and genetic predisposition. T cell antigen receptor V gene usage by T lymphocytes was investigated using four MAbs specific for various V gene products. One MAb (Ti3a), reactive with V beta 8 gene products, detected increased numbers of T cells in a subset of Crohn's disease patients as compared with normal controls and ulcerative colitis patients. In family studies there was no apparent inherited predisposition to the use of V beta 8 genes, and there was no association between a restriction fragment length polymorphism of the V beta 8.1 gene and Crohn's disease. The V beta 8+ T cells were concentrated in the mesenteric lymph nodes draining the inflammatory lesions and belonged to both the CD4+ and CD8+ T cell subsets. In contrast, lamina propria and intraepithelial T cells were not enriched in V beta 8+ T cells, suggesting that these cells were participating in the afferent limb of a gut-associated immune response. The expanded V beta 8+ T cells in Crohn's disease appear to result from an immune response to an as yet unknown antigen.