IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

Abstract

bIL12RB1 is a human gene that is important for resistance to Mycobacterium tuberculosis infection. IL12RB1 is expressed by multiple leukocyte lineages, and encodes a type I transmembrane protein (IL12R␤1) that associates with IL12p40 and promotes the development of host-protective T H 1cells. Recently, we observed that il12rb1-the mouse homolog of IL12RB1-is alternatively spliced by leukocytes to produce a second isoform (IL12R␤1⌬TM) that has biological properties distinct from IL12R␤1. Although the expression of IL12R␤1⌬TM is elicited by M. tuberculosis in vivo, and its overexpression enhances IL12p40 responsiveness in vitro, the contribution of IL12R␤1⌬TM to controlling M. tuberculosis infection has not been tested. Here, we demonstrate that IL12R␤1⌬TM represents a secreted product of il12rb1 that, when absent from mice, compromises their ability to control M. tuberculosis infection in extrapulmonary organs. Furthermore, elevated M. tuberculosis burdens in IL12R␤1⌬TM-deficient animals are associated with decreased lymph node cellularity and a decline in T H 1 development. Collectively, these data support a model wherein IL12R␤1⌬TM is a secreted product of il12rb1 that promotes resistance to M. tuberculosis infection by potentiating T H cells response to IL-12.

IL12Rβ1: The cytokine receptor that we used to know

“…We have recently turned our attention to whether IL12Rβ1ΔTM also enhances IL12p40-dependent responses of T H cells, as T H cells must express il12rb1 to limit experimental tuberculosis (117). The results of these experiments are forthcoming, but are consistent with a model wherein IL12Rβ1ΔTM expression serves to potentiate mouse leukocytes’ responses to IL12 (163). …”

Insights into IL-23 biology: From structure to function

“…Recently, it was shown that IL-12Rβ1ΔTM is a secreted product that promotes resistance to M. tuberculosis infection by potentiating T H cells response to IL-12 [50]. Ray and colleagues generated transgenic mice which do not express IL-12Rβ1ΔTM.…”

“…Furthermore, the IL-12Rβ1ΔTM deficient mice had decreased numbers of M. tuberculosis induced T H 1 cells. The authors proposed a model where secreted IL-12Rβ1ΔTM enhances the stability and/or bioavailability of IL-12 [50]. In humans, IL-12Rβ1 deficiency is a rare autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by poorly pathogenic mycobacteria and salmonella [47,51].…”

Differential expression of an alternative splice variant of IL-12Rβ1 impacts early dissemination in the mouse and associates with disease outcome in both mouse and humans exposed to tuberculosis

“…Dendritic cells in the lungs of Mtb-exposed mice produce not only IL-12p40 but also an alternative splice variant of IL-12Rβ1 which lacks the transmembrane domain and which we have called ΔTM-IL-12Rβ1 8 . This splice variant was identified when the receptor was first described 14 however its function was not appreciated until our studies in Mtb 8, 15 . The ΔTM-IL-12Rβ1 locates to the endoplasmic reticulum 16 and can be secreted by transfected cells and mitogen-activated T cells blasts 15 .…”

“…This splice variant was identified when the receptor was first described 14 however its function was not appreciated until our studies in Mtb 8, 15 . The ΔTM-IL-12Rβ1 locates to the endoplasmic reticulum 16 and can be secreted by transfected cells and mitogen-activated T cells blasts 15 . Human cells produce a similar splice variant of the IL12RB1 gene in response to Mtb exposure and this is referred to as isoform 2 8, 17 and has been shown to augment human T cell responsiveness to IL-12p70 18 .…”