Multiple Lymphocyte Subsets Research Articles

Anti-retroviral immunity

The mechanisms of immunity that protect from infection by viruses are being studied to help in vaccine design and immune intervention therapies. Research into retroviruses is often fuelled by the concern about HIV infection. Two papers 1 Hislop A.D. et al. Vaccine induced cytotoxic T lymphocytes protect against retroviral challenge. Nat. Med. 1998; 4: 1193-1196 Crossref PubMed Scopus (38) Google Scholar , 2 Dittmer U. Brooks D.M. Hasenkrug K.J. Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection. Nat. Med. 1999; 5: 189-193 Crossref PubMed Scopus (81) Google Scholar have recently been published that show the wide difference in results obtained with two different retrovirus infections. The first study used a peptide of a cytotoxic T lymphocyte (CTL) epitope to immunize sheep against bovine leukemia virus (BLV) 1 Hislop A.D. et al. Vaccine induced cytotoxic T lymphocytes protect against retroviral challenge. Nat. Med. 1998; 4: 1193-1196 Crossref PubMed Scopus (38) Google Scholar . All the immunized sheep showed anti-peptide CTL (CD8+ T-cell) responses, but only ∼50% showed anti-viral CTL responses; these animals were protected from an intravenous challenge with BLV- infected cells. There was no evidence of any other type of immune mechanism (antibody or CD4+ T-cell) involvement in protection. The second study used a murine retrovirus model, Friend virus (which is a mix of two viruses), a replication-competent helper virus and the replication-defective pathogenic virus 2 Dittmer U. Brooks D.M. Hasenkrug K.J. Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection. Nat. Med. 1999; 5: 189-193 Crossref PubMed Scopus (81) Google Scholar . Immune spleen cells from mice were immunized with an attenuated vaccine virus, separated into CD4+, CD8+ T cells or CD19+ B cells, and adoptively transferred into naive recipients to see which subsets provided protection against an intravenous virus challenge. Although CD8+ T cells could help to clear infection, they did not prevent establishment of infection and the appearance of persistently infected cells. All three cell types were necessary together to see protection from acute and persistent infection.

Requirement for multiple lymphocyte subsets in protection by a live attenuated vaccine against retroviral infection.

Infection by live attenuated retroviruses provides excellent protection from challenge with pathogenic viruses in several animal models, but little is known about which immune effectors are necessary for protection. We examined this using adoptive transfer experiments in the Friend virus mouse model. Transfers of immune spleen cells into naive mice conferred complete protection, and transfers of purified lymphocyte subsets demonstrated that this effect required complex immune responses involving CD4+ and CD8+ T cells and also B cells. In addition, passive immunization experiments demonstrated that antibodies alone reduced virus loads but did not prevent infection. These findings may have implications for retroviral vaccine design in general.

A novel pathway of thymus-directed T lymphocyte maturation.

Recent evidence has indicated that the intestinal epithelium may be a major extrathymic site of T cell production. However, which of the multiple intestinal intraepithelial lymphocyte (IEL) subsets are extrathymic in origin has been controversial. We now report that the thymus is an integral component of IEL maturation and is required for a novel two-stage process of T cell production. Thus, in neonatally thymectomized mice TCR-gamma delta IELs were depleted and some TCR-alpha beta IELs were of an immature phenotype. Thymus grafting experiments revealed that all TCR-gamma delta and TCR-alpha beta IEL subsets could be thymus-derived, including TCR-alpha beta cells lacking Thy1 and CD8 beta. In utero anti-TCR-gamma delta mAb treatments resulted in depletion of gamma delta IEL without subsequent re-emergence of this subset in adulthood, whereas anti-TCR-alpha beta mAb treatment only marginally reduced the alpha beta IEL subset. These findings suggest that TCR-alpha beta and TCR-gamma delta IELs arose at distinct developmental stages. Overall, the results indicate that some IEL precursors are thymus-derived but require further thymic influence to mature in the periphery.