CD8 T cells specific for human immunodeficiency virus, Epstein-Barr virus, and cytomegalovirus lack molecules for homing to lymphoid sites of infection.

CD8 T cells are classified as naïve, effector, or memory cells on the basis of CD45RA, CD62L, and CCR7 expression. Sequential engagement of cell-surface CD62L and CCR7 receptors is required for efficient trafficking to lymphoid tissue by means of high endothelial venules. Naïve CD8 T cells are CCR7(+)CD62L(+) CD45RA(+), whereas long-term memory cells are CCR7(+)CD62L(+)CD45RA(-). Effector cytotoxic T cells are thought to be CCR7(-)CD45RA(+). The distribution of CD8 subsets and cytolytic protein expression in healthy donors and donors seropositive for human immunodeficiency virus (HIV) were compared. In HIV-infected subjects, CCR7(-) CD8 T cells expanded at the expense of naïve and long-term memory cells. In both healthy donors and HIV-infected donors, CCR7(+) CD8 T cells were uniformly negative for perforin. In all subsets, perforin and granzyme A were not coordinately expressed, with perforin expression being more tightly regulated. The properties of CD8 T cells specific for cytomegalovirus, Epstein-Barr virus (EBV), and HIV were studied by staining with major histocompatibility complex peptide tetramers. Antigen-specific cells for chronic infections with these viruses were uniformly CCR7(-) and predominantly CD62L(-). In 2 HIV-seropositive donors, 3- to 4-fold fewer EBV-tetramer-positive cells were present in lymph nodes compared with blood. Antigen-specific CD8 T cells are therefore preferentially excluded from lymphoid sites, even when infection is primarily in lymphoid tissue. This may protect lymphoid tissues from immunopathological changes but compromise immune defense against viruses, such as HIV and EBV, that target lymphocytes. HIV-specific CD8 T cells do not express CD45RA, whereas EBV- and CMV-specific CD8 T cells are heterogeneous in CD45RA(+) expression. Lack of CD45RA expression may indicate incomplete differentiation of HIV-specific CD8 T cells to cytotoxic T cells.

[1]  J. Lieberman,et al.  Viral-specific cytotoxic T lymphocytes lyse human immunodeficiency virus-infected primary T lymphocytes by the granule exocytosis pathway. , 1999, Blood.

[2]  J. Lieberman,et al.  Recognition of a small number of diverse epitopes dominates the cytotoxic T lymphocytes response to HIV type 1 in an infected individual. , 1997, AIDS research and human retroviruses.

[3]  L. Picker,et al.  Lymphocyte Homing and Homeostasis , 1996, Science.

[4]  J. Schmitz,et al.  Emergence of CTL coincides with clearance of virus during primary simian immunodeficiency virus infection in rhesus monkeys. , 1999, Journal of immunology.

[5]  W. Blattner,et al.  HIV infection--induced posttranslational modification of T cell signaling molecules associated with disease progression. , 1996, The Journal of clinical investigation.

[6]  J. Saukkonen,et al.  Expansion of a CD8+CD28- cell population in the blood and lung of HIV-positive patients. , 1993, Journal of acquired immune deficiency syndromes.

[7]  F. Sallusto,et al.  Two subsets of memory T lymphocytes with distinct homing potentials and effector functions , 1999, Nature.

[8]  T. Kuijpers,et al.  Cytolytic Mechanisms and Expression of Activation-Regulating Receptors on Effector-Type CD8+CD45RA+CD27− Human T Cells , 2000, The Journal of Immunology.

[9]  D. Speiser,et al.  Cutting Edge: Cytolytic Effector Function in Human Circulating CD8+ T Cells Closely Correlates with CD56 Surface Expression1 , 2000, The Journal of Immunology.

[10]  Hans Hengartner,et al.  Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice , 1994, Nature.

[11]  M. Rep,et al.  Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells , 1997, The Journal of experimental medicine.

[12]  J. Lieberman,et al.  Perforin is not co-expressed with granzyme A within cytotoxic granules in CD8 T lymphocytes present in lymphoid tissue during chronic HIV infection. , 1999, AIDS.

[13]  B. Walker,et al.  HIV-1 gag-specific cytotoxic T lymphocytes recognize multiple highly conserved epitopes. Fine specificity of the gag-specific response defined by using unstimulated peripheral blood mononuclear cells and cloned effector cells. , 1991, Journal of immunology.

[14]  J. Lieberman,et al.  Impaired function of circulating HIV-specific CD8(+) T cells in chronic human immunodeficiency virus infection. , 2000, Blood.

[15]  U. V. von Andrian,et al.  The Cc Chemokine Thymus-Derived Chemotactic Agent 4 (Tca-4, Secondary Lymphoid Tissue Chemokine, 6ckine, Exodus-2) Triggers Lymphocyte Function–Associated Antigen 1–Mediated Arrest of Rolling T Lymphocytes in Peripheral Lymph Node High Endothelial Venules , 2000, The Journal of experimental medicine.

[16]  Douglas D. Richman,et al.  HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function , 2000, The Journal of experimental medicine.

[17]  E. Butcher,et al.  The Role of Chemokines in the Microenvironmental Control of T versus B Cell Arrest in Peyer's Patch High Endothelial Venules , 2000, The Journal of experimental medicine.

[18]  C. Mackay,et al.  Naive and memory T cells show distinct pathways of lymphocyte recirculation , 1990, The Journal of experimental medicine.

[19]  Paul C. Rogers,et al.  From Naive to Memory T Cells , 1996, Immunological reviews.

[20]  B. Autran,et al.  Unusually high frequencies of HIV-specific cytotoxic T lymphocytes in humans. , 1989, Journal of immunology.

[21]  G. Ogg,et al.  Direct Visualization of Antigen-specific CD8+T Cells during the Primary Immune Response to Epstein-Barr Virus In Vivo , 1998, The Journal of experimental medicine.

[22]  E. Wolf,et al.  CCR7 Coordinates the Primary Immune Response by Establishing Functional Microenvironments in Secondary Lymphoid Organs , 1999, Cell.

[23]  Circulating CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Individuals Have Impaired Function and Downmodulate CD3ζ, the Signaling Chain of the T-Cell Receptor Complex , 1998 .

[24]  B. Walker,et al.  HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes , 1998, Nature.

[25]  H. Yonekawa,et al.  A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4. , 1998, Blood.

[26]  M A Nowak,et al.  Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. , 1998, Science.

[27]  Philip J. R. Goulder,et al.  Phenotypic Analysis of Antigen-Specific T Lymphocytes , 1996, Science.

[28]  B. Walker,et al.  HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals. , 1988, Science.

[29]  X. Jin,et al.  The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL , 1996, Journal of virology.

[30]  D. Pillay,et al.  Direct visualization and quantitation of cytomegalovirus-specific CD8+ cytotoxic T-lymphocytes in liver transplant patients. , 2000, Transplantation.

[31]  M. Roederer,et al.  CD8 naive T cell counts decrease progressively in HIV-infected adults. , 1995, The Journal of clinical investigation.

[32]  T. Springer.  Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm , 1994, Cell.

[33]  C. Hallahan,et al.  Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors , 2000, The Journal of Immunology.

[34]  R. Zinkernagel,et al.  Immunological Memory , 2006 .

[35]  P. Nibbering,et al.  Decreased expression of zeta molecules by T lymphocytes is correlated with disease progression in human immunodeficiency virus-infected persons. , 1999, The Journal of infectious diseases.

[36]  P. Henkart,et al.  Cytotoxic cells : basic mechanisms and medical applications , 2000 .

[37]  J. Lieberman,et al.  CD3zeta and CD28 down-modulation on CD8 T cells during viral infection. , 2000, Blood.

[38]  J. Lieberman,et al.  CD3ζ and CD28 down-modulation on CD8 T cells during viral infection , 2000 .

[39]  B. Walker,et al.  HIV-specific cytotoxic T lymphocytes in seropositive individuals , 1987, Nature.

[40]  J. Rodgers,et al.  Anergy and apoptosis in CD8+ T cells from HIV-infected persons. , 1994, Journal of immunology.

[41]  A. Kumar,et al.  Immediate Early and Early Lytic Cycle Proteins Are Frequent Targets of the Epstein-Barr Virus–induced Cytotoxic T Cell Response , 1997, The Journal of experimental medicine.

[42]  C. Tournay,et al.  Characterization of CMVpp65-specific CD8+ T lymphocytes using MHC tetramers in kidney transplant patients and healthy participants. , 2000, Transplantation.

[43]  B. Autran,et al.  AIDS virus-specific cytotoxic T lymphocytes in lung disorders , 1987, Nature.

[44]  J. Lieberman,et al.  Human Immunodeficiency Virus-Specific Circulating CD8 T Lymphocytes Have Down-Modulated CD3ζ and CD28, Key Signaling Molecules for T-Cell Activation , 2000, Journal of Virology.

[45]  J. Lieberman,et al.  Three regions of HIV-1 gp160 contain clusters of immunodominant CTL epitopes. , 1996, Immunology letters.

[46]  J. Tschopp,et al.  Appearance of granule-associated molecules during activation of cytolytic T-lymphocyte precursors by defined stimuli. , 1988, Immunology.

[47]  A. Fauci,et al.  Expression of HLA class I-specific inhibitory natural killer cell receptors in HIV-specific cytolytic T lymphocytes: impairment of specific cytolytic functions. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[48]  M. Johnson,et al.  Lymphocyte activation in HIV‐1 infection. II. Functional defects of CD28− T cells , 1994, AIDS.

[49]  M. Roederer,et al.  8 color, 10-parameter flow cytometry to elucidate complex leukocyte heterogeneity. , 1997, Cytometry.

[50]  M. Gunn,et al.  A high endothelial cell-derived chemokine induces rapid, efficient, and subset-selective arrest of rolling T lymphocytes on a reconstituted endothelial substrate. , 1998, Journal of immunology.

[51]  E. Butcher,et al.  6-C-kine (SLC), a Lymphocyte Adhesion-triggering Chemokine Expressed by High Endothelium, Is an Agonist for the MIP-3β Receptor CCR7 , 1998, The Journal of cell biology.

[52]  W. Lee,et al.  Memory B and T cells. , 1991, Annual review of immunology.