T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease

doi:10.1016/0167-5699(88)91215-7

Immunology Today

Volume 9, Issues 7–8, 1988, Pages 207-213

Immunology Today

https://doi.org/10.1016/0167-5699(88)91215-7 Get rights and content

Abstract

The response of F₁ hybrid mice to the injection of parental T cells depends upon, among other things, the genetic make up of donor and host. In most cases, inoculation results in the development of lethal graft-versus-host disease in the recipient, but under certain circumstances a condition resembling human lupus erythematosus ensues. According to Charles Via and Gene Shearer, an analysis of these lupus-inducing crosses suggests that disease is the result of a deficient cytotoxic T-cell response that is unable to control the proliferation of autoantibody-producing B cells. A better understanding of these murine model systems may allow the defects behind the human condition to be identified.

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To test the relative roles of perforin (pfp) vs. FasL in CTL control of autoreactive B cell expansion, we used the parent-into-F1 model of murine graft-vs.–host disease in which donor CD8 CTL prevent lupus like disease by eliminating activated autoreactive B cells. F1 mice receiving either pfp or FasL defective donor T cells exhibited an intermediate short-term phenotype. Pairing of purified normal CD4 T cells with either pfp or FasL defective CD8 T cell subsets resulted in impaired host B cell elimination and mild lupus like disease that was roughly equivalent in the two experimental groups. Thus, in addition to major roles in tumor and intracellular pathogen control, pfp mediated CD8 CTL killing plays a significant role in controlling autoreactive B cell expansion and lupus downregulation that is comparable to that mediated by FasL killing. Importantly, both pathways are required for optimal elimination of activated autoreactive B cells.
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Citation Excerpt :
Importantly, if parental CD8 T cells are administered in addition to CD4 T cells and the disparity between parent and F1 involves both MHC I and II, disease phenotype is converted from a lupus-like chronic GVHD to an acute lethal disease in which donor CD8 T cells mature into CTL specific for host MHC I. The resulting attack on host immune and hematopoetic system results in a profound immunodeficiency that can be lethal [21,22]. Thus, lupus-like disease in this model is thought to result solely from the activation of an oligoclonal population of alloreactive donor CD4 T cells specific for host MHC II and that concurrent activation of donor CD8 T cells qualitatively alters disease phenotype such that B cells are eliminated and lupus-like disease is prevented [21].
Lupus-like renal disease in DBA/2-into-F1 (DBA → F1) mice is driven by donor CD4 T cells and is more severe in females. Donor CD8 T cells have no known role. As expected, we observed that females receiving unfractionated DBA splenocytes (CD8 intact → F1) exhibited greater clinical and histological severities of renal disease at 13 weeks compared to males. Surprisingly, sex-based differences in renal disease severity were lost in CD8 depleted → F1 mice due to an improvement in females and a worsening in males. CD8 intact → F1 female mice exhibited significantly greater donor and host effector (CD44^hi, CD62L^lo) CD4 T cells and ICOS^hi CD4 T follicular helper cells than males. CD8 depleted → F1 female mice exhibited a reduction in the absolute numbers of host, but not donor CD4 Tfh cells and lost the significant increase in host CD4 effector cells vs. males. Greater female IL-21 expression, a product of Tfh cells, was seen in CD8 intact → F1 and although reduced was still greater than male CD8 depleted → F1 mice. Thus, donor CD8 T cells have a critical role in mediating sex-based differences in lupus renal disease severity possibly through greater host ICOS^hi CD4 T cell involvement.
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Citation Excerpt :
The basics of the parent-into-F1 (P→F1) model and its resemblance to human lupus have been examined [1–4].
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RostrumT-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease

Abstract

Immunol. Today

J. Exp. Med.

J. Immunol.

J. Immunol.

J. Exp. Med.

J. Immunol.

J. Immunol.

J. Exp. Med.

Eur. J. Immunol.

J. Immunol.

J. Exp. Med.

J. Immunol.

J. Exp. Med.

Eur. J. Immunol.

Rostrum
T-cell interactions in autoimmunity: insights from a murine model of graft-versus-host disease