Abstract CMVs are β herpesviruses that establish lifelong latent infection of their hosts. Acute infection of C57BL/6 mice with murine CMV elicits a very broad CD8 T cell response, comprising at least 24 epitopes from 18 viral proteins. In contrast, we show here that the CD8 T cell response in chronically infected mice was dominated by only five epitopes. Altogether, four distinct CD8 T cell kinetic patterns were evident. Responses to some epitopes, including M45, which dominates the acute response, contracted sharply after day 7 and developed into stable long-term memory. The response to m139 underwent rapid expansion and contraction, followed by a phase of memory inflation, whereas the response to an M38 epitope did not display any contraction phase. Finally, responses against two epitopes encoded by the immediate early gene IE3 were readily detectable in chronically infected mice but near the limit of detection during acute infection. CD8 T cells specific for the noninflationary M45 epitope displayed a classic central memory phenotype, re-expressing the lymph node homing receptor CD62L and homeostatic cytokine receptors for IL-7 and IL-15, and produced low levels of IL-2. Responses to two inflationary epitopes, m139 and IE3, retained an effector memory surface phenotype (CD62Llow, IL-7Rα−, IL-15Rβ−) and were unable to produce IL-2. We suggest that immunological choices are superimposed on altered viral gene expression profiles to determine immunodominance during chronic murine CMV infection.
Increasing amounts of pathogen replication usually lead to a proportionate increase in size and effector differentiation of the CD8+ T cell response, which is attributed to increased Ag and inflammation. Using a murine CMV that is highly sensitive to the antiviral drug famciclovir to modulate virus replication, we found that increased virus replication drove increased effector CD8+ T cell differentiation, as expected. Paradoxically, however, increased virus replication dramatically decreased the size of the CD8+ T cell response to two immunodominant epitopes. The decreased response was due to type I IFN-dependent depletion of conventional dendritic cells and could be reproduced by specific depletion of dendritic cells from day 2 postinfection or by sterile induction of type I IFN. Increased virus replication and type I IFN specifically inhibited the response to two immunodominant epitopes that are known to be dependent on Ag cross-presented by DCs, but they did not inhibit the response to "inflationary" epitopes whose responses can be sustained by infected nonhematopoietic cells. Our results show that type I IFN can suppress CD8+ T cell responses to cross-presented Ag by depleting cross-presenting conventional dendritic cells.
To assess the effect of herpes simplex virus (HSV) on assembly and transport of class I MHC molecules, we compared class I MHC immunoprecipitated from metabolically labeled infected and uninfected human dermal fibroblasts. The immunoprecipitates were analyzed by isoelectric focusing, allowing identification of individual class I alleles and assessment of transport through the Golgi apparatus by the sialation of carbohydrate residues. In cells infected with wild-type HSV, class I synthesis was reduced or abolished because of the host protein synthesis shutoff function of the UL41 gene product. In cells infected with mutant viruses of both HSV-2 strain G and HSV-1 strain 17 that lack the UL41 gene, class I HLA molecules failed to become sialated, suggesting that they were not transported to the Golgi apparatus. In contrast, transferrin receptor was normally sialated in both infected and uninfected cells. Drug treatments of cells to restrict viral gene expression suggested that an early gene or genes were responsible for the effect. A pulse chase showed that class I molecules were synthesized in normal amounts in infected cells, but that heavy chains were retained in a sialyl transferase negative compartment either stably associated with beta 2m or as free heavy chain in a pattern that is characteristic for each class I allele. HSV is thus the fourth example of a DNA virus that interferes with class I assembly or transport.
Abstract Using immunohistochemical methods, we have analysed colorectal biopsies of normal mucosa, metaplastic polyps (5 cases), adenomas (15 cases) and adenocarcinomas (70 cases) with 13 monoclonal antibodies (MAbs) to allelic products of the HLA‐A, B, C loci. Nine of the 70 carcinomas showed total loss of HLA Class‐I molecules due to an underlying defect regarding not only the expression of β 2 ‐microglobulin (·β 2 ‐m), but also the heavy chains of HLA A, B and C loci, or both. Much commoner was a loss of one or more Class‐I alleles as follows: Al/Aw36 (completely lost in 4 of 29 cases and focally lost in another 2), A2 (in 1 of 37 cases), A3 (in 2 of 14 cases), A11/28/31/33 (in 3 of 11 cases), B7 (in 3 of 13 and focally in 1 other case), B17 (in 1 case), Bw4 (in 8 of 45 and focally in another 6), Bw6 (in 9 of 62 and focally in another 3). Focal selective loss (Bw6 and a combined A 1 ‐Bw6), was observed in 2 adenomas. Normal colonic mucosa, as well as stromal and lymphoid cells present between the neoplastic glands, were studied in each case as a control. A particular allele was only considered to be lost by the malignant cells if it was still expressed on these adjacent tissues.
Abstract In previous studies of antigen presentation through HLA‐B27, we identified a healthy person whose lymphoblastoid cells do not present three B27‐restricted viral epitopes to specific cytotoxic T lymphocytes (CTL), despite adequate cell surface expression of HLA‐B2702 of normal sequence. Similar findings were observed in all members of his family sharing the HLA‐A3‐B2702 haplotype. The original donor, NW, carries HLA‐B8 on his other class I haplotype, which his daughter, HW, has inherited. We now report a failure to present an HLA‐B8‐restricted epitope from influenza nucleoprotein following viral infection of NW cells, although exogenous added peptide is still presented normally. However, cells from HW, which do not carry the A3‐B2702 haplotype, present the expected epitope after viral infection. Another B8‐restricted epitope, from human immunodeficiency virus‐gag, is presented equally well by both cell lines when infected with gag‐vaccinia. This antigen processing phenotype does not correlate with any of the known human TAP‐1 and TAP‐2 polymorphisms.
Human CMV (HCMV) is a ubiquitous pathogen that indelibly shapes the NK cell repertoire. Using transcriptomic, epigenomic, and proteomic approaches to evaluate peripheral blood NK cells from healthy human volunteers, we find that prior HCMV infection promotes NK cells with a T cell-like gene profile, including the canonical markers CD3ε, CD5, and CD8β, as well as the T cell lineage-commitment transcription factor Bcl11b. Although Bcl11b expression is upregulated during NK maturation from CD56
ABSTRACT CMV, a ubiquitous herpesvirus, elicits an extraordinarily large T cell response that is sustained or increases over time, a phenomenon termed ‘memory inflation.’ Remarkably, even latent, non-productive infection can drive memory inflation. Despite intense research on this phenomenon, the infected cell type(s) involved are unknown. To identify the responsible cell type(s), we designed a Cre-lox murine CMV (MCMV) system, where a spread-deficient (ΔgL) virus expresses recombinant SIINFEKL only in Cre+ host cells. We found that latent infection of endothelial cells (ECs), but not dendritic cells (DCs) or hepatocytes, was sufficient to drive CD8 T cell memory inflation. Infection of Lyve-1-Cre and Prox1-CreER T2 mice revealed that amongst EC subsets, infection of lymphatic ECs was sufficient. Genetic ablation of β2m on lymphatic ECs did not prevent inflation, suggesting another unidentified cell type can also present antigen to CD8 T cells during latency. This novel system definitively shows that antigen presentation by lymphatic ECs drives robust CD8 T cell memory inflation. SUMMARY Active T cell immunosurveillance during latent CMV infection results in T cell ‘memory inflation.’ A novel Cre-lox genetic system for cell-specific antigen expression reveals that lymphatic ECs, but not DCs or hepatocytes, can drive CD8 T cell memory inflation.
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