https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71142-9.pdf

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo.

Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

We have established a murine model system for exploring the ability of a CD4 subset-deficient host to cope with cytomegalovirus infection, and reported three findings. First, an antiviral response of the CD8 subset of T lymphocytes could be not only initiated but also maintained for a long period of time despite a continued absence of the CD4 subset, whereas the production of antiviral antibody proved strictly dependent upon help provided by the CD4 subset. Second, no function in the defense against infection could be ascribed as yet to CD4-CD8- T lymphocytes, which were seen to accumulate to a new subset as a result of depletion of the CD4 subset. This newly arising subset did not substitute for CD4+ T lymphocytes in providing help to B lymphocytes, and was also not effective in controlling the spread of virus in host tissues. As long as a function of these cells in the generation and maintenance of a CD8 subset-mediated response is not disproved, caution is indicated with concern to an autonomy of the CD8 subset. Third, even though with delay, the CD8+ effector cells raised in the CD4 subset-deficient host were able of clear vital tissues from productive infection and to restrict asymptomatic, persistent infection to acinar glandular epithelial cells in salivary gland tissue.

https://rupress.org/jem/article-pdf/169/4/1199/1098943/1199.pdf

Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes.

Background Cytomegalovirus (CMV) disease in immunocompromised patients correlates with a deficiency of CD8+ cytotoxic T lymphocytes specific for CMV. We evaluated the safety and immunologic effects of immunotherapy with clones of these lymphocytes in recipients of allogeneic bone marrow transplants. Methods Clones of CD8+ cytotoxic T cells specific for CMV proteins were isolated from the blood of bone marrow donors. Fourteen patients each received four intravenous infusions of these clones from their donors beginning 30 to 40 days after marrow transplantation. The reconstitution of cellular immunity against CMV was monitored before and during the period of infusions and for up to 12 weeks after the final infusion. The rearranged genes encoding the T-cell receptor served as markers in evaluating the persistence of the transferred T cells. Results No toxic effects related to the infusions were observed. Cytotoxic T cells specific for CMV were reconstituted in all patients. In vitro measurements showed that ...

Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor

We have shown in a murine model system for acute, lethal cytomegalovirus (CMV) disease in the immunocompromised natural host that control of virus multiplication in tissues, protection from virus-caused tissue destruction, and survival are mediated by virus-specific CD8+ CD4-T lymphocytes. Protection from a lethal course of disease did not result in a rapid establishment of virus latency, but led to a long-lasting, persistent state of infection. The CD8- CD4+ subset of T lymphocytes was not effective by itself in controlling murine CMV (MCMV) multiplication in tissue or essential for the protective function of the CD8+ CD4- effector cells. The antiviral efficacy of the purified CD8+ CD4- subset was not impaired by preincubation with fibroblasts that presented viral structural antigens, but was significantly reduced after depletion of effector cells specific for the nonstructural immediate-early antigens of MCMV, which are specified by the first among a multitude of viral genes expressed during MCMV replication in permissive cells. Thus, MCMV disease provides the first example of a role for nonstructural herpesvirus immediate-early antigens in protective immunity.

https://epub.ub.uni-muenchen.de/6652/1/Koszinowski_Ulrich_6652.pdf

CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity.

Interstitial pneumonia associated with viral replication in lung tissue was observed after cytomegalovirus infection of total-body gamma-irradiated mice, whereas in noncompromised hosts the lungs were not affected and virus multiplication was restricted to the salivary glands. The radiation damage could either predispose normally nonpermissive cell types for productive infection or abrogate an immune control of the tissue manifestation of infection by elimination of lymphocytes. Adoptive transfer of lymphoid cells into irradiated, infected recipients supported the second alternative. Even when infection was established in the lungs, as manifested by the presence of infected lung tissue cells in the alveolar septa, an antiviral effect could be assigned to the Lyt-2+, L3T4- subset of T lymphocytes specifically sensitized in the immunocompetent donor. These cells did not require in vitro propagation to perform effector cell functions in vivo and were operative under physiological conditions in comparatively low numbers. Hence, there is reason to assume that T lymphocytes are responsible for the tissue distribution of cytomegalovirus replication during infection.

Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs.

Peptides that are antigenic for T lymphocytes are ligands for two receptors, the class I or II glycoproteins that are encoded by genes in the major histocompatibility complex, and the idiotypic alpha/beta chain T-cell antigen receptor. That a peptide must bind to an MHC molecule to interact with a T-cell antigen receptor is the molecular basis of the MHC restriction of antigen-recognition by T lymphocytes. In such a trimolecular interaction the amino-acid sequence of the peptide must specify the contact with both receptors: agretope residues bind to the MHC receptor and epitope residues bind to the T-cell antigen receptor. From a compilation of known antigenic peptides, two algorithms have been proposed to predict antigenic sites in proteins. One algorithm uses linear motifs in the sequence, whereas the other considers peptide conformation and predicts antigenicity for amphipathic alpha-helices. We report here that a systematic delimitation of an antigenic site precisely identifies a predicted pentapeptide motif as the minimal antigenic determinant presented by a class I MHC molecule and recognized by a cytolytic T lymphocyte clone.

/pdf/a-pentapeptide-as-minimal-antigenic-determinant-for-mhc-4i47axjbcx.pdf

A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes.

CD8+ T cells are the main effector cells for the immune control of cytomegaloviruses. To subvert this control, human and mouse cytomegaloviruses each encode a set of immune-evasion proteins, referred to here as immunoevasins, which interfere specifically with the MHC class I pathway of antigen processing and presentation. Although the concerted action of immunoevasins prevents the presentation of certain viral peptides, other viral peptides escape this blockade conditionally or constitutively and thereby provide the molecular basis of immune surveillance by CD8+ T cells. The definition of viral antigenic peptides that are presented despite the presence of immunoevasins adds a further dimension to the prediction of protective epitopes for use in vaccines.

/pdf/antigens-and-immunoevasins-opponents-in-cytomegalovirus-4vn2dq9pr8.pdf

Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance.

The existence of four subpopulations in resting porcine T lymphocytes is documented. In addition to the two known subpopulations which are typified by a mutually exclusive expression of either the CD8 or the CD4 differentiation antigen, CD4-CD8+ and CD4+CD8- T lymphocytes, respectively, two unusual subpopulations were prominent not only in peripheral blood, but also in lymphoid tissues: CD4-CD8- T lymphocytes expressing neither of these antigens and CD4+CD8+ T lymphocytes coexpressing both antigens. While CD4+CD8+ lymphoblasts have been found also in other species, resting T lymphocytes with that phenotype are without precedent among all species analyzed to date. This unique composition of the porcine T lymphocyte population has to be taken into consideration when the swine is used as a large animal model in experimental medicine.

https://epub.ub.uni-muenchen.de/6742/1/Koszinowski_Ulrich_6742.pdf

Matthias J. Reddehase

Papers

CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity.

Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs.

A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes.

Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance.

Simultaneous expression of CD4 and CD8 antigens by a substantial proportion of resting porcine T lymphocytes