When everything is working well, a finely tuned T cell-dependent antibody (B cell) response maximizes immunity and minimizes damage to the host. However, when that response goes awry, it can precipitate numerous immunological disorders, including systemic lupus erythematosus (SLE) and B cell lymphoma. Although the roles played by the MHC class II proteins in T cell-dependent autoimmunity are fairly well understood, those played by the MHC class I proteins are not. A Jackson Laboratory research team led by Professor Derry Roopenian, Ph.D. wanted to rectify that situation. Roopenian and his colleagues recently reported that some key MHC class I proteins – notably cluster of differentiation 8 alpha (CD8A) and interleukin 15 (IL15) – dramatically slow down the progression of SLE-like disease in the BXSB/MpJ (000740) mouse and of B cell lymphoma in the SJL/J (000686) mouse (McPhee et al. 2011). Therapies that amplify the functions of these proteins could considerably ameliorate autoimmune diseases in humans.
SLE and B cell lymphomas are MHC class II-driven diseases caused by uncontrolled and autoreactive CD4+ T cell-dependent B cell responses. Roopenian and his colleagues wanted to know if MHC class I proteins also play a role. First, because most MHC class I proteins cannot function without associating with the B2-microglobulin (B2M) chain, the researchers produced a B2M-deficient version of the SLE model BXSB/MpJ mouse (see photo and description below). They found that, compared to the BXSB/MpJ mouse, which lives 32 weeks, the B2M-deficient BXSB/MpJ mouse lives only 18 weeks, indicating that some MHC class I molecules slow down the progression of SLE-like disease in the BXSB/MpJ mouse. To determine which specific MHC class 1 proteins are responsible, the researchers compared the life spans among BXSB/MpJ mice deficient for one of each of the following MHC class 1 proteins: CD1D1 (needed to produce IL4-secreting NKT cells), FCGRT (plays a role in antigen presentation), H2-K and H-2D (responsible for antigen presentation), and TAP1 (loads processed antigens onto H2-K and H2-D). Roopenian and his colleagues found that only the life spans of H2-K/D- and TAP1-deficient mice are shorter than those of BXSB/MpJ mice (25 and 23 weeks respectively vs 32 weeks).
Given that H2-K/D- and TAP1-deficient mice have abnormally low numbers of CD8+ T cells, the researchers wanted to know what the role of these cells is in the SLE-like pathology of the BXSB/MpJ mouse. So, they produced a CD8A-deficient BXSB/MpJ mouse and found that its survival curve is between those for BXSB/MpJ and B2M-deficient BXSB/MpJ mice, indicating that CD8A is at least partly responsible for slowing down disease progression.
The BXSB/MpJ mouse (000740) develops a severe T/B cell-dependent, SLE-like, chronic, late onset autoimmunity that results from the interaction between the autosomal genetic BXSB background and strong amplifying effects of the Y-linked autoimmune accelerating gene mutation, Yaa. The mouse lives for an average of only 32 weeks.
Given that IL15 supports memory CD8+ T cells and NK cells, the researchers constructed an IL15-deficient BXSB/MpJ mouse and found that it also does not live as long as the BXSB/MpJ mouse, indicating that IL15 also plays a role in slowing down disease progression.
The researchers then produced a double knockout (DKO) BXSB/MpJ mouse deficient for both CD8A and IL15 and found that it, like the B2M-deficient BXSB/MpJ mouse, lives for only about 18 weeks. That result led the Roopenian team to conclude that the accelerated disease progression of the B2M-deficient BXSB/MpJ mouse is due to the additive effects of CD8A- and IL15-deficiency – in other words, a weakened CD8/NK axis. When functional, this regulatory axis acts like a brake and slows down disease progression.
The Roopenian team then compared a battery of autoimmune disease phenotypes among BXSB/MpJ, B2M-deficient BXSB/MpJ, and DKO mice to those of the autoimmune disease-resistant control strain, BXSB.B6-Yaa+/J (000742). Their results strongly suggested that DKO and B2M-deficient BXSB/MpJ mice die from the same ICOS+ CD4+ T cell-dependent IL21-driven disease that characterizes the BXSB/MpJ mouse. Roopenian and his team substantiated this hunch by demonstrating that both the DKO and the B2M-deficient BXSB/MpJ mice deficient for IL21R stay healthy and survive for at least 40 weeks.
Because considerable evidence indicates that CD8+ regulatory T (Treg) cells control immune disorders, the Roopenian team compared the CD8+ Treg populations from the spleens of BXSB/MpJ and BXSB.B6-Yaa+/J controls. They found that BXSB/MpJ spleens contain significantly more CD8+ Treg cells that express CD122 and IL15A, both components of IL15R, substantiating IL15's importance in slowing the progression of SLE-like disease in the BXSB/MpJ mouse. These CD8+ Treg cells also express Ly49, which are known to suppress autoimmune disease.
The Roopenian team suspected that the same MHC class 1-associated CD8/NK axis also slows the progression of B cell lymphoma in the SJL/J mouse (000686). So, they performed experiments similar to those described with the BXSB/MpJ mouse: They compared the life spans of B2M-, CD1D1-, FCGRT-, CD8A-, Perforin- (PRF1)-, and IL15-deficient SJL mice. They observed that, compared to regular SJL mice, which live 50 weeks, B2M-deficient SJL mice live only 42 weeks, and CD8A- and PRF1-deficient SJL mice live about 46 weeks. The similar effects of CD8A- and PRF1-deficiency suggested that the overall protective effects conferred by B2M are largely perforin-dependent. Histopathologic and molecular studies of moribund SJL mice, B2M-deficient SJL mice, and CD8A-deficient SJL mice conducted by the Roopenian team further substantiated their hypothesis that disrupting the CD8/NK axis also accelerates the development of the MHC class 2-driven B lymphomas of SJL mice.
In summary, Professor Roopenian and his colleagues demonstrated that though the SLE-like disease of the BXSB/MpJ mouse and the B cell lymphomas of the SJL/J mouse are MHC class 2-driven, MHC class 1 proteins act like brakes and slow down the progression of these pathologies. Therefore, therapies that augment the protective effects of MHC class 1 proteins may help treat or prevent MHC class 2-driven diseases in humans.