[eng] Tryptophan (TRP) has been linked to the immune response mainly through the
immunosuppressive activities of indoleamine 2, 3-dioxygenase (IDO). Here we show
evidence that TRP acts as a biochemical signal from damaged cells that attracts and
enables immune responses. TRP levels above 2-3mol/L are essential for T-Lymphocyte
proliferation, but it has never been previously established whether normal physiological
levels of TRP are sufficiently low to limit T-Lymphocyte proliferation. Although blood
plasma TRP in humans varies from 30 to 65mol/L, most of this TRP is bound to protein
so free-TRP levels are much lower. Interstitial fluid levels of drugs and metabolites are
generally regarded as being similar to plasma free-levels. Human cerebrospinal fluid
(CSF) TRP levels vary from 0.9 to 3.3mol/L in non-inflammatory conditions, but
albumin is also present at levels of 1.5 to 5.2mol/L and able to bind TRP in a 1 : 1 ratio.
Using ultrafiltration, we measured free TRP levels in CSF from 10 non-inflammatory
patients and found these were 22% lower than total TRP in these same patients. This indicated a normal reference interval of 0.5 to 2.9mol/L for CSF free-TRP which is
either below or bordering upon the threshold for T-Lymphocyte proliferation previously
determined in tissue culture medium. We also measured free TRP in 4 patients with
central nervous system inflammatory disease and found free-TRP levels of 0.5+/-0.3
which were well below the threshold.
Activated T-lymphocytes in inflammatory conditions release -interferon, which
induces IDO in a wide range of different cells including epithelial cells, fibroblasts,
dendritic cells, neurones, astrocytes, microglia, trophoblasts and macrophages. IDO is
able to lower TRP levels below the threshold for T-lymphocyte proliferation, thus acting
as a TRP noise suppression system and feedback control mechanism. Here we show that
neutrophils exhibit strong TRP chemotaxis, migrating towards higher TRP levels, which
raises the possibility that other myeloid and lymphoid cells might also migrate in a TRP
gradient. We observed that freeze-thaw damaged liver tissue slices or fresh slices
incubated with Staphylococcus aureus or Escherichia coli produce very large quantities
of TRP along with other amino acids. We propose that the TRP signal arises from
damaged tissue, raising TRP levels well above the threshold for T-lymphocyte
proliferation, that IDO dampens signal noise by removing excess TRP, highlighting
inflammatory foci, maintaining a TRP gradient for inward chemotaxis of neutrophils and
possibly other immune cells.