A Case of Hypersensitivity to Mosquito Bites with Type III Latency of EB Virus Infection in NK Cells with Prolonged Survival Due to Induction of Specific CD8+ Cytotoxic T Cells.
Shigeru TsuchiyaWei DuHídeaki KikutaToru UchiyamaMasaei OnumaTakeshi RikiishiYoji SasaharaMiyako Yoshinari OhuchiMasayoshi MinegishiSatoru Kumaki
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HIV-specific cytotoxic T lymphocytes (CTL) are thought to play a major role in viral control in HIV-infected adults. Changes in the relative proportions of CD8 lymphocyte subpopulations are also thought to be associated with disease progression. Less is known about the relative effectiveness of CTL against different HIV targets, or about the relationship, if any, between CTL activity and CD8 subpopulations. We have measured CTL activity against four HIV gene products (gag, tat, pol and env) and expression of CD45RO, CD45RA, HLA-DR, CD29, S6F1, and CD57 surface markers on CD8 cells from nine HIV-infected and 11 HIV-uninfected children. Of nine HIV-infected children, six showed antigen-specific CTL activity on at least one occasion: 4/6 directed against tat, 6/6 against pol, 1/6 against env, and 1/6 against gag. However, the specificity of the CTL activity varied between children and within individual children with time. Furthermore, two uninfected children showed CTL activity, one to HIV-gag, -pol and -tat, and the other to HIV-pol. All the HIV-infected and two uninfected children had abnormal proportions of CD8 subpopulations in whole blood compared with age-matched controls. There was no correlation between CTL activity and CD8 subsets in whole blood. Five children changed from CTL-positive to CTL-negative (or vice versa) during the study. In these, the occasions when CTL activity was detected coincided with an increase in CD8 cells, an expansion of HLA-DR+ CD8 cells and a loss of CD45RA+ CD8 cells.
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The immunosuppressive drug Cyclosporin A (cyclosporine) inhibits the reactivation of quiescent Ag-dependent CTL in the presence of IL-2. Both proliferation and the regeneration of cytotoxicity are inhibited. The cytotoxic cells that are inhibited are Ag dependent for activation, whereas derived, Ag-independent, but still IL-2-dependent, cytotoxic cells are insensitive to cyclosporine. Cyclosporine also directly inhibits the effector phase of the cytotoxic cells, although not completely. The generation of primary CTL in mixed cultures was also blocked by cyclosporine in the presence of IL-2, in a time-dependent way that indicated that the sensitive time was early during the cultures. The CTL generated in primary cultures were significantly inhibited by cyclosporine in the assay, but this inhibition was less than for the cloned CTL lines.
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It has been assumed that the maturation of pre-CTL to virus-specific effector CTL is dependent upon IL-2-mediated T cell triggering through the IL-2R. In view of its similarity to IL-2 in its effects on immune cells, we sought to determine whether IL-15 can induce the expansion of AIDS virus-specific pre-CTL to mature CTL. PBL of SIV(mac)-infected rhesus monkeys or HIV-1-infected humans have previously been shown to expand to effector CTL when cultivated with a predicted CTL epitope peptide and rIL-2. We now demonstrate that rIL-15 facilitates this expansion of effector CTL. In fact, rIL-15-driven expansion of virus-specific CTL occurs in the presence of IL-2-neutralizing or anti-IL-2R Abs, indicating that this cellular maturation can occur in an IL-2-independent fashion. These studies suggest a mechanism by which CTL may be capable of expanding in vivo in the absence of IL-2 and functional CD4+ T lymphocytes.
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Abstract A limiting dilution assay was used to compare the frequency of cytotoxic T lymphocyte precursors (CTL‐P) which respond to H‐2 antigens presented with additional background differences, with the frequency of CTL‐P which respond to H‐2 antigens on a self background. Individual cultures were divided and assayed for cytotoxic activity on the two targets sharing H‐2, but not the background; no cultures were seen which clearly killed one and not the other, and the same frequency of CTL‐P was measured on target cells that differed from the responder only at H‐2 and on target cells that differed also in the background, irrespective of the background of the stimulator. Thus, the assumption that allospecific cytotoxic T lymphocytes (CTL) recognize H‐2 plus minor histocompatibility antigens does not serve as an adequate explanation for the high frequency of allospecific CTL. The data also suggest that the two allelic forms of β 2 ‐microglobulin do not contribute to the alloantigenic determinant.
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Abstract We have previously shown that human endothelial cells (EC) are less efficient than professional APC, e.g., B lymphoblastoid cells (BLC), at stimulating allogeneic CD8+ T cells to develop into CTL. In this study we describe FACS-based limiting dilution analyses using the dilution of the intracellular dye CFSE as an indicator of CD8+ T cell alloactivation and expansion with significantly increased sensitivity compared with conventional, cytotoxicity-based assays. In addition, this assay permits the relative size of clonal CTL populations that are generated in individual CD8+ T cell cultures to be determined (clonal burst size). We have applied this method to quantitatively compare the generation of CTL at the clonal level following stimulation of allogeneic CD8+ T cells by either BLC or HUVEC derived from the same donor. CD8+ T cells expanded by allostimulation were identified as CD8+, CFSElow cells and were categorized as CTL by the expression of intracellular perforin and IFN-γ. Precursor frequencies for EC-stimulated CTL were 5- to 40-fold (mean, 7.5-fold) lower compared with BLC-stimulated CTL (p < 0.01). Concomitantly, the average clonal burst sizes in EC-stimulated CTL cultures were significantly smaller than those in conventional CTL cultures, primarily due to the occurrence of some very large clone sizes exclusively with BLC stimulation. Although EC-stimulated CTL were generated only from the memory subset of CD8+ T cells, BLC-stimulated very large burst sizes of CTL were observed from both naive and memory CD8+ T cell precursors. These data establish that both a lower frequency of reactive precursors and more limited clonal expansion, but not regulatory T cells, contribute to the reduced capacity of EC to promote alloreactive CTL differentiation compared with that of professional APC.
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A limiting‐dilution system was established to measure the frequency of alloreactive cytotoxic T‐lymphocyte precursors (CTL‐p) in human peripheral blood T cells. Culture medium supple mented with recombinant interleukin‐2 enabled clonal expansion of all CTL‐p stimulated by allogeneic peripheral blood or spleen cells. The range of CTL‐p frequencies in fully HLA‐mismatched responder‐stimulator combinations was 1:240 to 1:1230. Split‐well analysis of individual microwells showed that the cytotoxic T‐cell clones generated under limiting‐dilution conditions showed exquisite specificity for the stimulating alloantigens. Alloreactive CTL‐p were enriched in the OKT4 T‐cell subset. This limiting‐dilution system was highly reproduci ble and can thus be applied to investigate human cytotoxic T‐eell precursor frequencies in various clinically relevant situations.
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A population of CD8+ CTL can be generated in vitro in the presence of anti-CD8 mAb. Due to their apparent high avidity characteristic, these anti-CD8-resistant CD8+ CTL may have important functional in vivo roles in graft rejection, and may be important in antiviral and antitumor responses. We have previously reported that this anti-CD8-resistant subset of CD8+ CTL demonstrates functional differences from anti-CD8-sensitive CD8+ CTL. One important difference between the subsets is the markedly greater dependence of anti-CD8-resistant CTL upon exogenous cytokines for their generation in vitro. In this study, we have investigated in detail the cytokine requirements for the generation of allospecific CD8+ CTL in vitro and have found that IL-4 can augment the generation of anti-CD8-sensitive but not anti-CD8-resistant CTL, whereas IL-2 or IL-12 can augment the generation of both anti-CD8-sensitive and anti-CD8-resistant CTL. However, anti-CD8-resistant CTL require at least 10-fold higher concentrations of IL-2 than do anti-CD8-sensitive CTL. This more stringent IL-2 requirement precludes the efficient generation of anti-CD8-resistant CTL in vitro in the absence of exogenous IL-2 because they cannot produce sufficient IL-2 to meet their needs, in contrast to anti-CD8-sensitive CTL. By providing exogenous cytokines to allospecific CTL generation cultures, we further demonstrate that anti-CD8-resistant CTL can be functionally skewed to the Tc1 subset, but differ from anti-CD8-sensitive conventional CTL in that they cannot be skewed to the Tc2 subset.
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