Differential Migration of T Lymphocytes into Different Areas of the CNS

Juan J. Lafaille

New York University Medical Center

Funded in December, 2001: $300000 for 3 years
LAY SUMMARY . ABSTRACT . SELECTED PUBLICATIONS .

ABSTRACT

back to top

Differential Migration of T Lymphocytes into Different Areas of the CNS

We have recently described that two distinct and stable T helper 2 (Th2) subpopulations can be obtained from the same naïve T cell precursors depending on the presence or absence of small amounts of IFN-γ at the time of priming. The two Th2 subpopulations vary in the ratio of IL-4 to IL-5 that they produce, and throughout this application are referred to as Th2 (normal levels of IL-4 and IL-5) and Th2Hi5 (high ratio of IL-5 to IL-4).

Interestingly, when injected into RAG-/- mice, myelin basic protein (MBP)-specific T cells belonging to both Th2 subpopulations caused an inflammatory disease in the recipient mice, but the disease outcomes were very different depending upon which Th2 subpopulation was injected. While Th2 cells induced the well-known ascending paralysis that progresses from the tail through the hind legs toward the front legs (heretofore referred to as "classical" experimental autoimmune encephalomyelitis or classical EAE), Th2Hi5 cells induced a severe inflammatory disease which could not be scored according to the conventional disease scale. Animals receiving Th2Hi5 cells would roll on their back, spin and display great difficulty in maintaining the right position. We refer to this disease as "non-classical" EAE. Thus, T cells with identical specificity for MBP, primed under slightly different conditions are capable of causing clinically different diseases.

Examination of the various parts of the central nervous system (CNS) by histology or FACS revealed that the inflammatory infiltrate predominated in the spinal cord in animals afflicted with classical EAE, but predominated in the brainstem and cerebellum in animals that displayed non-classical EAE. Moreover, the inflammatory cells observed in the non-classical EAE lesions were very enriched in eosinophils, whereas the inflammatory cells observed in classical EAE lesions displayed large numbers of neutrophils and mononuclear cells (when classical EAE was induced with Th2 cells) or a predominance of mononuclear cells (when classical EAE was induced with Th1 cells).

To explain our data, we hypothesize that T lymphocytes primed in an IFN-γ-poor microenvironment (Th2Hi5) acquire the property to migrate into cerebellum/brainstem, whereas T lymphocytes with identical antigen specificity but primed in the presence of IFN-γ (Th1 or conventional Th2) preferentially migrate to the spinal cord. We further hypothesize that adhesion/homing molecules, and in particular chemokines and chemokine receptors, may be differentially expressed, accounting for the differential lymphocyte migration.

In order to explore these possibilities, our Specific Aims are:

1. To determine chemokine and chemokine receptor profiles in T cells primed in the absence of IFN-γ or in its presence and to determine whether chemokine expression in different parts of the normal CNS can explain the preferential attraction of the two Th2 cell subtypes.

2. To determine the role of IL-5-mediated eosinophilia in the non-classical EAE pathology.

3. To block specific chemokine/chemokine receptor interactions in order to re-direct lymphocyte migration onto different parts of the CNS. Vertigo is a known occurrence in some MS patients and is often accompanied by brainstem inflammation. At least with regard to some clinical and histological aspects, non-classical EAE may serve as a model for inflammation-triggered vertigo. Furthermore, we believe that the non-classical EAE, which we can reproducibly induce, represents a novel model to help understand the mechanisms underlying differential migration of immune cells into the different tissues of the central nervous system.

SELECTED PUBLICATIONS

back to top

Wensky A.K., Furtado G.C., Marcondes M.C., Chen S., Manfra D., Lira S.A., Zagzag D., and Lafaille J.J.  IFN-gamma determines distinct clinical outcomes in autoimmune encephalomyelitis.  J Immunol. 2005 Feb 1;174(3):1416-23