The fate of mature T lymphocytes might be a lot more flexible than previously thought. New research from the RIKEN Center for Allergy and Immunology (RCAI) in Japan and La Jolla Institute for Allergy and Immunology (LIAI) in the USA shows for the first time that mature CD4+ helper T lymphocytes can be re-programed to become killer-like CD8+ T lymphocytes and gain killing functions.
The findings are reported in the journal Nature Immunology, by a team of researchers led by Ichiro Taniuchi from RIKEN and Hilde Cheroutre from La Jolla. The team show using transgenic mice that mature CD4+ helper T lymphocytes that have lost the transcription factor ThPOK express genes specific to CD8+ killer T lymphocytes upon exposure to a specific environmental stimulation such as the gut. This turns them into killer cells that might act to control infection.
CD4+ helper T lymphocytes and CD8+ killer T lymphocytes are important players in the body’s defense mechanism against infection. CD4+ helper T lymphocytes normally only assist other cells of the immune system during an infection, whereas CD8+ killer T cells are the main actors in the elimination of infected cells.
Both types of cells are generated in the thymus, where their early precursors develop first into cells bearing both CD4 and CD8 markers. These CD4+ CD8+ cells then differentiate into cells bearing either the CD4 or CD8 marker and take on either a helper (CD4+) or killer (CD8+) fate.
The transcription factor ThPOK is known to play a crucial role in the fate determination of T lymphocytes in the thymus. It represses genes specific to CD8+ cells in precursors of helper T cells and prevents these cells from differentiating into CD8+ killer cells. The expression of ThPOK continues in mature CD4+ helper T cells and is repressed in mature CD8+ cells.
In the study, Taniuchi, Cheroutre and colleagues show that upon deactivation of ThPOK, mature CD4+ T cells revert back to bearing both CD4 and CD8 markers in the mouse intestine. By analyzing RNA extracted from ThPOK-negative CD4+ CD8+ cells, the researchers demonstrate that the cells express various CD8+ cell-specific genes encoding for cytolitic proteins and that they have effectively differentiated into CD8+ killer T cells.
The authors conclude: “The unexpected plasticity of mature CD4+ T cells to differentiate into CD8+ cytolitic cells expands the functional capabilities of CD4+ T cells. It is possible that CD4+ T cells are also involved in direct protective functions and provide the immune system with an alternative protective mechanism.”
According to them, these cells may be recruited to help in the immune response at interfaces such as the skin or mucosae, where the rapid elimination of infected cells is crucial.
Taniuchi, I. Cheroutre, H. et al. “Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II–restricted cytotoxic T lymphocytes.” Nature Immunology, 2013, DOI: 10.1038/ni.2523