BLIMP1 increases its control over lymphocytes

The transcriptional repressor B-lymphocyte-induced maturation protein 1 (BLIMP1) is the 'master regulator' of the terminal differentiation of B cells into plasma cells. However, two papers published recently in Nature Immunology now report that BLIMP1 also has a key role in regulating T-cell homeostasis and activation.

Although the function of BLIMP1 in B cells has been well characterized, the function of BLIMP1 in other cell types has not been studied in detail. To address this gap in our knowledge, Kallies et al. generated BLIMP1-reporter mice, in which expression of a bicistronic DNA construct expressing the genes encoding green fluorescent protein (GFP) and a non-functional form of BLIMP1 was 'knocked in' to the gene encoding BLIMP1 (Prdm1). Mice homozygous for this construct lack BLIMP1 function and die in utero; therefore, subsequent analysis in this study was carried out using recombination-activating gene 1 (RAG1)-deficient mice reconstituted with fetal-liver cells from the knock-in mice (denoted Prdm1^gfp/gfp mice). By contrast, Martins et al. generated mice lacking BLIMP1 expression only in cells of the T-cell lineage (denoted CKO mice).

Both groups observed lymphocytic infiltration of the colon, lungs and liver, and tissue destruction indicative of colitis in the colon of their mice. Consistent with this inflammatory phenotype, CD4⁺ T cells from these mice produced more interferon-γ than control cells when stimulated in vitro and the total number of effector CD4⁺ T cells was increased in the spleen and lymph nodes of both Prdm1^gfp/gfp and CKO mice. Furthermore, analysis of GFP expression in CD4⁺ T cells from the Prdm1^gfp/gfp BLIMP1-reporter mice and Prdm1 mRNA in CD4⁺ T cells from wild-type mice indicated that among CD4⁺ T cells, effector cells expressed the highest levels of BLIMP1. Evidence that the phenotypes of colitis and an expanded effector CD4⁺ T-cell population were a result of BLIMP1 having an intrinsic T-cell function (that is, an intrinsic role in regulating T-cell homeostasis) was provided by several observations. First, naive CD4⁺ T cells from CKO mice, but not Prdm1^gfp/gfp mice, hyperproliferated when stimulated in vitro under sub-optimal conditions. Second, effector CD4⁺ and CD8⁺ T cells from Prdm1^gfp/gfp mice hyperproliferated when stimulated with CD3- and CD28-specific antibody in the presence of cytokines. Last, co-transfer of wild-type and Prdm1^gfp/gfp CD4⁺ T cells to RAG1-deficient mice resulted in the preferential expansion of the CD4⁺ T-cell population lacking functional BLIMP1.

Colitis and expanded effector CD4⁺ T-cell populations are also characteristics of mice lacking CD4⁺CD25⁺ regulatory T (T_Reg) cells. However, both Prdm1^gfp/gfp and CKO mice had T_Reg-cell populations, and these cells were functional in in vitro assays of regulatory function. By contrast, although T_Reg cells from Prdm1^gfp/gfp mice showed normal regulatory function in vivo, T_Reg cells from CKO mice had impaired regulatory function in vivo.

Although several points remain to be clarified (including defining the molecular mechanisms by which BLIMP1 mediates its effects in T cells, more precisely defining the T_Reg-cell phenotype in the absence of BLIMP1 and determining whether BLIMP1 has a role in T-cell development in the thymus), these two studies define a previously unknown function for BLIMP1 as a key regulator of T-cell homeostasis and activation.