Chemokines play a central role in regulating processes essential to the immune function of T cells1-3, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen T. gondii in the brains of chronically infected mice. This chemokine boosts T cell function in two different ways: it maintains the effector T cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Remarkably, these statistics are not Brownian; rather, CD8+ T cell motility in the brain is well described by a generalized Lévy walk. According to our model, this surprising feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T cell behavior is similar to Lévy strategies reported in organisms ranging from mussels to marine predators and monkeys4-10, and CXCL10 aids T cells in shortening the average time to find rare targets.

Peritoneal macrophages (PMs) from toll-like receptor 4 (TLR4)-deficient and wild-type (WT) mice were responsive to recombinant Toxoplasma gondii-derived heat shock protein 70 (rTgHSP70) and natural TgHSP70 (nTgHSP70) in NO release, but those from TLR2-, myeloid differentiation factor 88 (MyD88)-, and interleukin-1R-associated kinase 4 (IRAK4)-deficient mice were not. Polymyxin B did not inhibit PM activation by TgHSP70 and nTgHSP70 from WT and TLR4-deficient mice, while it inhibited PM activation by lipopolysaccharide. Pretreatment of PMs from WT but not from TLR4-deficient mice with rTgHSP70 resulted in suppression of NO release on restimulation with rTgHSP70. Similarly, pretreatment of PMs from WT but not TLR4-deficient mice with nTgHSP70 resulted in suppression of NO release on restimulation with nTgHSP70. Polymyxin B did not inhibit rTgHSP70- and nTgHSP70-induced tolerance of PMs from TLR4-deficient mice. Furthermore, PMs from WT mice increased suppressor of cytokine-signaling-1 (SOCS-1) expression after restimulation with rTgHSP70, while those from TLR4-deficient mice did not. Phosphorylation of JNK and I-κBα occurred in rTgHSP70-induced tolerance of PMs from TLR4-deficient mice, but not in that from WT mice. These data indicated that TgHSP70 signaling mechanisms were mediated by TLR2, MyD88, and IRAK4, but not by TLR4. On the other hand, signaling of TgHSP70-induced tolerance was mediated by TLR4, and the expression of SOCS-1 suppressed the TLR2 signaling pathway

Aimslbackground-To determine the functional properties and cytokine production profiles of melanoma specific cytotoxic T lymphocytes (CTLs) induced from peripheral blood leucocytes of two patients with Vogt-Koyanagi-Harada disease (VKH). Methods-Melanoma specific CTL lines were established by long term coculture with a human melanoma cell line (P-36). Cytotoxic activity against P-36 was measured by "Cr release. The involvement of human leucocyte antigen (HLA) class I or class II molecules in the cytotoxicity of the CTL lines against P-36 was analysed using anti-HLA class I or anti-HLA class II monoclonal antibody (MAb). Surface molecules of CTL lines were analysed by flow cytometry using MAbs specific for CD4, CD8, CD16, CD25, CD56, HLA-DR, T cell antigen receptor (TCR) ai and TCRy6. Cytokine production and soluble interleukin 2 receptor (sIL-2R) secretion were determined by enzyme linked immunosorbent assays. mRNAs of cytokines were analysed using reverse transcription polymerase chain reaction (RT-PCR). Results-CTLs showed strong cytotoxic activity against P-36. The CTL activity of the cell lines against P-36 was inhibited by the anti-HLA-DR MAb, whereas the MAb specific for monomorphic determinants of HLA-A, B, and C failed to block lytic activity. Flow cytometry identified the following surface molecules: CD4+, CD8-, CD16-, CD25+, CD56-, HLA-DR+, TCRa,x3", and TCRy&-. CTLs constitutively produced a high level of IL-6. IL-6 production and sIL-2R secretion of CTLs were enhanced when CTLs were stimulated with P-36. CTLs also produced high levels of interferon y (IFN-y) and IL-2, but not IL-4. mRNAs of IL-2 and IFN-y were detected by RT-PCR (HLA) phenotypes of these patients were as follows: patient 1 (SF male; 42 years) HLA-A24,

The maintenance of the T-cell response and the control of T. gondii in the eye during chronic infection is dependent on CXCL10.

Toxoplasma gondii -derived heat shock protein 70 (T.g.HSP70) induced maturation of bone marrow-derived dendritic cells (DCs) of wild-type (WT) C57BL/6 mice as evidenced by an increase in surface expression of MHC class I and II molecules and costimulatory molecules such as CD40, CD80, and CD86. Functionally, decreased phagocytic ability and increased alloreactive T cell stimulatory ability were observed in T.g.HSP70-stimulated DCs. These phenotypic and functional changes of T.g.HSP70-stimulated DCs were demonstrated in Toll-like receptor (TLR) 2-and myeloid differentiation factor 88 (MyD88)-deficient but not TLR4-deficient C57BL/6 mice. DCs from WT and TLR2-deficient but not TLR4-deficient mice produced IL-12 after T.g.HSP70 stimulation. T.g.HSP70-stimulated DCs from WT, TLR2-deficient, and MyD88-deficient, but not TLR4-deficient mice expressed IFN-␤ mRNA. Thus, T.g.HSP70 stimulates murine DC maturation via TLR4 through the MyD88-independent signal transduction cascade.