Cytotoxic T lymphocytes (CTL) seem to provide the major line of defence against many viruses. CTL effector functions are mediated primarily by cells carrying the CD8 (Ly-2) antigen (CD8+ cells) and are triggered by interactions of the T-cell receptor with an antigenic complex, often termed 'self plus X', composed of viral determinants in association with class I molecules of the major histocompatibility complex (MHC). The mechanism(s) of induction of virus-specific CTL in vivo is poorly understood, but data from in vitro experiments suggest that their generation is strictly dependent on functions provided by CD4+ helper T cells (also referred to as L3T4+; or TH) that respond to antigens in the context of class II (Ia) MHC determinants. The prevailing opinion that induction of most functions of CD8+ cells requires help provided by CD4+ cells has recently been challenged by the observation that CD8+ cells alone can mediate a variety of responses to alloantigens in vitro and in vivo; however, the possibility that CTL to self plus X could be generated in vivo in the absence of TH cells has not been evaluated. We report here that C57BL/6J (B6) and AKR/J mice, when functionally depleted of CD4+ cells by in vivo treatment with the CD4+-specific rat monoclonal antibody GK1.5 (refs 8-14) responded to ectromelia virus infection by developing an optimal in vivo virus-specific CTL response, and subsequently recovered from the disease (mousepox) that was lethal for similarly infected nude mice (CD4-, CD8-).
Antibody-producing cells display a special form of regulation whereby each cell produces immunoglobulin from only one of its two sets of antibody genes. This phenomenon, called allelic exclusion, is thought to be mediated by the product of one heavy chain allele restricting the expression of the other. Heavy chains are synthesized in two molecular forms, secreted and membrane bound. In order to determine whether it is specifically the membrane-bound form of the immunoglobulin M (IgM) heavy chain (mu) that mediates this regulation, transgenic mice were created that carry a human mu chain gene altered so that it can only direct the synthesis of the membrane-bound protein. The membrane-bound form of the human mu chain was made by most of the B cells in these animals as measured by assays of messenger RNA and surface immunoglobulins. Further, the many B cells that express the human gene do not express endogenous mouse IgM, and the few B cells that express endogenous mouse mu do not express the transgene. Thus, the membrane-bound form of the mu chain is sufficient to mediate allelic exclusion. In addition, the molecular structures recognized for this purpose are conserved between human and mouse systems.
Summary Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4R334X, as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient’s cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation.
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