Development, Dissemination, Distribution, and Plasticity of Memory CD8 T Cells

Brinkman, Charles Colin, Department of Microbiology, University of Virginia
Engelhard, Victor, Department of Microbiology, University of Virginia
McDuffie, Marcia, Department of Microbiology, University of Virginia
Ley, Klaus, Department of Biomedical Engineering, University of Virginia
Bender, Timothy, Department of Microbiology, University of Virginia
Erickson, Loren, Department of Microbiology, University of Virginia
Bullock, Timothy, Department of Pathology, University of Virginia

Bone marrow-derived dendritic cells (BMDC) traffic in a restricted manner in vivo when injected into mice and activate CD8 T cells in a small number of lymphoid organs (LO). We know that T cells activated in different LO express different patterns of homing receptors that mediate infiltration of different non-lymphoid tissues, and that BMDC immunization induces memory CD8 T cells. However, our understanding of the period between vaccination and memory is incomplete. In this work we used the restricted trafficking of BMDC in vivo to activate CD8 T cells in different LO, and examine the resulting distribution of those T cells among LO, their expression of tissue-specific homing receptors, and the development of memory T cells. We found that proliferated CD8 T cells redistributed into antigen-free lymph nodes (LN) within 3 days of activation. Despite heterogeneous expression of CD62L on redistributed cells, redistribution was sensitive to anti-CD62L. CD8 T cells that redistributed exhibited characteristics of fully differentiated effectors (IFN- production, CD127 neg ) comparable to splenic effectors. These cells also contained memory precursors. We also examined the expression of homing receptors on cells in the initial activation site and after redistribution to Ag-free LN. 41 integrin was induced on CD8 T cells activated in mesenteric and mediastinal LNs and was retained after they redistributed into antigen-free axillary/brachial LN. Similarly, the 1B11 epitope of CD43 and E-selectin ligand (ESL) were induced on CD8 T cells activated in axillary/brachial LN and were retained upon redistribution into antigenfree mesenteric and mediastinal lymph nodes. Redistributed cells also did not acquire "new" homing molecules characteristic of the sites into which they migrated. Additionally, homing molecules induced during activation were maintained on memory T ii cells. Alpha41+ memory cells primed in mediastinal LN and spleen distributed systemically, while 1B11/ESL+ memory cells primed in cutaneous LN preferentially resided in cutaneous LN. When reactivated, memory cells retained 41 or 1B11/ESL and also acquired new homing molecules. These results indicate that BMDC immunization provides powerful specificity in the programming of primary responses, and in the distribution and homing receptor expression of resting memory T cells, while allowing for flexibility upon re-challenge.

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PHD (Doctor of Philosophy)
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