MHC class II expression through a hitherto unknown pathway supports T helper cell-dependent immune responses: implications for MHC class II deficiency

Abstract

IntroductionMHC class II (MHCII) molecules play a pivotal role in the development of protective T-cell immunity by displaying antigenic peptides from the endocytic pathway to CD4 ϩ T helper (Th) cells. 1 MHCII gene expression is tightly regulated and mostly restricted to thymic epithelium 2,3 and professional antigenpresenting cells (APCs) [4][5][6] but inducible also in other cell types. Coordinated expression of all MHCII genes is controlled by a conserved promoter region. 7,8 This promoter contains the socalled X, X2, and Y boxes, which bind the heterotrimeric RFX complex 9 consisting of RFX5, RFXAP, and RFXANK, 10-13 CREB (cAMP-responsive element-binding protein), [14][15][16] and NF-Y. 17 Transcriptional activity of MHCII genes is, however, not only dependent on these DNA-binding molecules but requires the cell type-specific 18,19 or inducible presence 20,21 of the transcriptional coactivator CIITA. 22 Defects in one of the genes of the RFX proteins or CIITA led to almost complete absence of MHCII expression. This phenomenon was first observed in a human hereditary immunodeficiency, called MHCII deficiency or bare lymphocyte syndrome (BLS). 5,23,24 BLS patients have reduced Th-cell numbers and are extremely susceptible to infections with bacterial, viral, and fungal pathogens. 25 The development of Th-cell-dependent class-switched immunoglobulin responses is impaired in these patients, despite reports of residual MHCII expression on B-cell lines from some patients and the presence of CD4 ϩ T cells. 26,27 It seems unlikely that the Th cells of BLS patients develop in the thymus since the thymic cortex, which is normally responsible for positive selection, showed no MHCII expression in BLS patients. [28][29][30] To date, the only available treatment for this fatal disease is allogeneic BM transplantation (BMT), which in the case of BLS has a low success rate. 27,31 To further investigate the mechanisms underlying this immunodeficiency and to test novel treatment strategies, we and others have generated mouse models of BLS by inactivating the genes coding for CIITA and for RFX5. [32][33][34][35] Similar to the human disease, CIITA Ϫ/Ϫ and RFX5 Ϫ/Ϫ mice lack MHCII expression on the majority of peripheral APCs. Unexpectedly, residual MHCII expression was found in the thymic medulla, on a subset of dendritic cells (DCs) in peripheral lymphoid organs, and on in vitro-activated RFX5 Ϫ/Ϫ B cells. Due to the absence of MHCII in thymic cortex, both mutants are unable to generate Th cells and thus fail to mount Th-cell-dependent immune responses. [32][33][34] To test whether the residual MHCII expression in RFX5 Ϫ/Ϫ and CIITA Ϫ/Ϫ mice ("BLS mice"), and potentially also in Patients, materials, and methods Mouse maintenance and typingRFX5 Ϫ/Ϫ mice 33 and CIITA Ϫ/Ϫ mice 32 were on a mixed 129/Ola/C57BL/6 or 129/Sv/C57BL/6 background, respectively, and were intercrossed to generate CR Ϫ/Ϫ mice. The double knock out was confirmed by polymerase chain reaction (PCR) and Southern blot. For the RFX5 deficiency, the primers RFX...

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