Andrew L. Mellor

A Requirement for the Rho-Family GTP Exchange Factor Vav in Positive and Negative Selection of Thymocytes

The T cell repertoire is shaped by positive and negative selection of thymocytes that express low levels of T cell receptor (TCR) and both CD4 and CD8. TCR-mediated signals that determine these selection processes are only partly understood. Vav, a GDP-GTP exchange factor for Rho-family proteins, is tyrosine phosphorylated following TCR stimulation, suggesting that it may transduce TCR signals. We now demonstrate that mice lacking Vav are viable and display a profound defect in the positive selection of both class I- and class II-restricted T cells. In contrast, Vav is not essential for negative selection, though in its absence negative selection is much less effective. Vav may influence the efficiency of TCR-induced selection events by regulating the intracellular calcium flux of thymocytes.

Recognition of Db and Kb gene products by influenza-specific cytotoxic T cells.

A series of 16 H-2b-restricted, A influenza virus-specific cytotoxic T-cell clones are described and characterized. One is Kb restricted, the others Db restricted. The factors governing Kb or Db restriction patterns seen in the mixed populations from which clones are derived are investigated. The Kb-restricted clone does not recognize Kb mutant bm1 and influenza and all 15 Db-restricted clones do not recognize Db mutant bm14 and A influenza virus; these results are discussed in the light of findings in a variety of other viral systems. Representative Kb- and Db-restricted clones were used to assess the functional properties of cloned cosmids containing either Kb or Db genes expressed in transformed L-cells (κ haplotype). The expression products of both cosmids functioned efficiently as mutually exclusive restriction elements for A influenza virus recognition.

Sooty foot, a novel mouse mutation that affects the pigmentation of exposed skin, but not hair, maps to Chromosome 2

We have characterized a novel recessive mouse mutation, named sooty foot, that increases the pigmentation of the exposed skin on the foot pads, the genital region, around the snout and muzzle, the ears, and the tail. By contrast, the pigmentation of the hair is unaffected. We have localized the mutation to Chromosome 2 by polymerase chain reaction (PCR) amplification of simple sequence repeats from pooled DNA from backcross progeny. In an extended backcross we have generated a detailed map of the region around sooty foot.This novel recessive mutation, sooty foot (soo), occurred in the inbred strain CBA during transgenic experiments, although it is not caused by transgenic insertion into the genome. The mutation has no apparent effect on hair pigmentation, but darkens the pigmentation of the non-hairy skin of the ears, tail, and other locations and greatly increases pigmentation of the ventral feet and footpad. Using the DNA pooling method of Taylor (Taylor et al. 1994), we localized soo to Chr 2 and have accurately mapped the mutation within the central part of that chromosome.

EDITORIAL: Induction of Immunological Tolerance to Self

In this editorial I will first review evidence in support of the clonal deletion hypothesis, which explains tolerance in terms of selection against developing self-reactive T and B cells, and the proceed, to discuss recent evidence that tolerance can be imposed, in some circumstances, on mature T and B cells in the extra-thymic and bone marrow compartment