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T Cells in Cryptopatch Aggregates Share TCR Variable Region Junctional Sequences with T Cells in the Small Intestinal Epithelium of Mice¹

Bradley S. Podd^2,*,, Joseph Thoits^2,, Nicholas Whitley, Hao-Yuan Cheng, Kimberly L. Kudla^*, Hiroko Taniguchi, Joanna Halkias, Kerstin Goth and Victoria Camerini^3,

^* Department of Pediatrics, University of Virginia Health Sciences Center, Charlottesville, VA 22908; Department of Pediatrics and Department of Surgery, Childrens Hospital Los Angeles, and Saban Research Institute, University of Southern California, Los Angeles, CA 90027; and Department of Pediatrics and the Center for Immunology, University of California, Irvine, CA 92697

The role of cryptopatch aggregates in the development of intestinal intraepithelial lymphocytes (IEL) is a matter of controversy. Therefore, an important question is whether T cells in cryptopatch aggregates are lineally related to IEL. We hypothesized that if ⁺ IEL derive from T cells in cryptopatch aggregates, then a clonal relationship would exist between the two populations. To test this hypothesis, we compared the sequence of rearranged TCR gamma variable region 5 genes in ⁺ IEL and cryptopatch cells. We purified IEL by FACS and cryptopatch cells were isolated from frozen sections of the intestine by laser-assisted microdissection. PCR showed that TCR gamma variable region 5 was rearranged in ⁺ IEL and in CD3⁺ cryptopatch cells, but not in CD3^– cryptopatch cells. DNA sequence analysis showed that the frequency of in-frame junctions in cryptopatch aggregates was at a level consistent with positive selection in both wild-type and athymic nude mice. In addition, the predicted amino acid sequences of V-J junctions present in ⁺ IEL and cryptopatch cells were encoded by identical nucleotide sequences. By contrast, the frequency of in-frame joints was significantly reduced in cryptopatch cells isolated from TCR -deficient mice, indicating that the enrichment of in-frame joints in cryptopatch cells must normally depend on expression of surface TCR. Our results are consistent with the hypothesis that a subset of ⁺ IEL are related to T cells in cryptopatch aggregates. The precise role of cryptopatch aggregates in intestinal ⁺ T cell homeostasis still needs to be determined.