Title page for ETD etd-06112009-063145
|Type of Document
||Goté, Lisa R.
||Alternate pathways of cytotoxic T lymphocyte and natural killer cell activation
||Master of Science
|Nagarkatti, Prakash S.
|Date of Defense
CD44 is a transmembrane glycoprotein found on a variety of cells including
those of myeloid and lymphoid origin. CD44 is highly conserved among various
species and is involved in the homing of lymphocytes and monocytes to lymph
nodes, Peyer's patches, and sites of inflammation. In the present study, we
demonstrate that monoclonal antibody (mAb) 9F3, directed against murine CD44
expressed on cytotoxic T lymphocytes (CTls), can trigger the lytic activity of CTls
and redirect CTl-mediated lysis to antigen-negative Fc receptor-positive target cells.
Similar redirected lysis was also inducible using mAb MEL - 14, directed against the
lymphocyte homing receptor for endothelium (gp - 90MEL-14). The redirected lysis
induced by mAbs 9F3 and MEl-14 in the CTL was similar to that induced by mAbs
against the aβ T-cell receptor or CD3. In contrast, mAbs directed against CDS,
CD45R, and CD11a (LFA-1, lymphocyte function-associated antigen 1) failed to evoke
lytic activity. Furthermore, CD44 and MEl-14 mAbs were able to mediate NK cell
lysis of the NK-resistant tumor PS15. The current study demonstrates that CD44 and
gp_90MEL-14 molecules, in addition to participating in T-cell homing and adhesion, may
play a major role in delivering the transmembrane signal to the CTl that triggers the
lytic activity, even when the T cell receptor is not occupied. The alternate pathway
of CTL activation characterized in this study may exhibit both beneficial and
deleterious effects on the host. On one hand, this property may enable CTL to kill
cancer cells or virally-infected cells which may fail to express major
histocompatibility complex (MHC)-encoded antigens. On the other hand, this
alternate pathway may contribute to nonspecific tissue damage seen at sites of
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