IFN-γ from CD4 T Cells Is Essential for Host Survival and Enhances CD8 T Cell Function during Mycobacterium tuberculosis Infection

Abstract

IFN-γ is necessary in both humans and mice for control of Mycobacterium tuberculosis (M. tuberculosis). CD4 T cells are a significant source of IFN-γ during acute infection in mice and are required for control of bacterial growth and host survival. However, several other types of cells can and do produce IFN-γ during the course of the infection. We sought to determine whether IFN-γ from sources other than CD4 T cells was sufficient to control M. tuberculosis infection and whether CD4 T cells had a role in addition to IFN-γ production. To investigate the role of IFN-γ from CD4 T cells, a murine adoptive transfer model was developed in which all cells were capable of producing IFN-γ, with the exception of CD4 T cells. Our data in this system support that CD4 T cells are essential for control of infection but also that IFN-γ from CD4 T cells is necessary for host survival and optimal long-term control of bacterial burden. In addition, IFN-γ from CD4 T cells was required for a robust CD8 T cell response. IFN-γ from T cells inhibited intracellular replication of M. tuberculosis in macrophages, suggesting IFN-γ may be necessary for intracellular bactericidal activity. Thus, although CD4 T cells play additional roles in the control of M. tuberculosis infection, IFN-γ is a major function by which these cells participate in resistance to tuberculosis.

Cellular Requirements for Systemic Control of Salmonella enterica Serovar Typhimurium Infections in Mice

“…Furthermore, these results imply that cognate stimulation and clonal expansion of specific CD4 ϩ T cells (51) may be uncoupled from IFN-␥ production and that other CD4 ϩ T cell-mediated effector mechanisms probably contribute to bacterial clearance (50). Interestingly, very similar observations have recently also been reported during murine infections with Mycobacterium tuberculosis (52)(53)(54)(55). Nevertheless, to conclusively answer what other effector mechanisms contribute or are necessary for bacterial clearance the development of a mouse model for the selective absence of IFN-␥ in CD4…”

CXCL5-secreting pulmonary epithelial cells drive destructive neutrophilic inflammation in tuberculosis

“…We did not detect changes in pulmonary M. tuberculosis-specific type 1 CD4 and CD8 T cell responses following highdose infection of Cxcl5 -/-mice despite reduced PMN recruitment. Similarly, Cxcr2 -/-mice devoid of PMNs in BAL fluid showed improved resistance to high-dose M. tuberculosis infection, which argues against defective type 1 T cell responses (56). Differential experimental setups, notably low-versus high-dose M. tuberculosis inocula, appear to influence the outcome of PMN-governed host defense.…”

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

“…Although IL12R␤1⌬TM is expressed by both innate and adaptive lineages (24,26), our recent demonstration that il12rb1 gene products must be expressed by rag1-dependent lineages for TB control to occur (32) supports a model wherein T cell expression of IL12R␤1⌬TM, and not innate expression, is primarily responsible for IL12R␤1⌬TM's protective effects in extrapulmonary sites. Therefore, it will be important to understand IL12R␤1⌬TM's mechanism in the context of T H 1 cell biology and how the balance between IL12R␤1 and IL12R␤1⌬TM fine-tunes the T H 1 response, since this lineage is required for TB control (33). where IL-12 is limiting.…”