Journal of Clinical Immunology, Vol. 27, No. 2, March 2007 ( C  2007) DOI: 10.1007/s10875-007-9077-z γδ T Lymphocytes—Selectable Cells Within the Innate System? WILLI K. BORN, 1,2 NIYUN JIN, 1 M. KEMAL AYDINTUG, 1 J. M. WANDS, 1 JENA D. FRENCH, 1 CHRISTINA L. ROARK, 1 and REBECCA L. O’BRIEN 1 Received January 16, 2007; accepted January 22, 2007 Published online: 14 February 2007 Lymphocytes expressing γδ T cell receptors (TCR) constitute an entire system of functionally specialized subsets that have been implicated in the regulation of immune responses, includ- ing responses to pathogens and allergens, and in tissue repair. The γδ TCRs share structural features with adaptive receptors and peripheral selection of γδ T cells occurs. Nevertheless, their specificities may be primarily directed at self-determinants, and the responses of γδ T cells exhibit innate characteristics. Contin- uous cross talk between γδ T cells and myeloid cells is evident in histological studies and in in vitro co-culture experiments, suggesting that γδ T cells play a functional role as an integral component of the innate immune system. KEY WORDS: γδ T cell; T cell receptor; ligand; innate lymphocyte; Subset. INTRODUCTION The conceptual lines between innate and adaptive im- munity are drawn clearly (1). Adaptive immunity devel- ops during the lifetime of an individual as a response to antigen-exposure or a particular infection. It is mediated by lymphocytes expressing selectable antigen receptors. The adaptive response tends to confer specific protective immunity, i.e. increased resistance to re-infection with the same pathogen, but it can also mediate autoimmu- nity. In contrast, innate immunity is common to an entire species, and it develops in a genetically programmed fash- ion, which is hardly modified by an individual’s history. It is mediated by cells expressing nonselectable pattern- recognition receptors (2). Although very powerful in the short term, the innate response does not confer long- 1 Department of Immunology at National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206. 2 National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206; e-mail: bornw@njc.org. lasting protective immunity, nor does it mediate autoim- munity. Most cells of the immune system can be readily clas- sified as innate or adaptive. All myeloid cells including granulocytes, monocytes, macrophages, and myeloid den- dritic cells, and some lymphocytes, lymphoid dendritic cells, and natural killer cells are considered innate cells, whereas αβ T lymphocytes and B lymphocytes are mostly considered adaptive cells. However, some of the lympho- cytes do not fit the adaptive categories as well, despite their expression of selectable antigen receptors. These include B1 B cells, NKT cells, and γδ T cells, and γδ T cells represent a special case because of their reliance on their own separate set of receptor genes (3, 4). Rather than being a specialized subset of a larger and mostly antigen-specific and adaptive lymphocyte population, γδ T cells form an independent population of lymphocytes. In fact, the population of γδ T lymphocytes itself represents a complex system of developmentally and functionally differentiated subsets (5). This seems to be true in all vertebrate species studied so far. However, the present re- view is mostly limited to studies in rodents and primates, with a focus on the much-investigated murine system of γδ T cells. In this review, the question of whether γδ T cells themselves should be considered innate or adaptive will be addressed first. Second, the question of how γδ T cells interface with the system of innate cells will be examined, focusing on potential differences to classical adaptive lymphocytes such as antigen-specific αβ T cells. SELECTION OF γδ T CELLS Like lymphocytes of the adaptive system, γδ T cells carry antigen-receptors assembled by a mechanism of re- combination and insertion that vary in the physical prop- erties of their putative ligand-binding sites. In fact, calcu- lating recombinatorial possibilities at the level of genes in the mouse revealed that γδ TCRs have a greater potential 133 0271-9142/07/0300-0133/0 C  2007 Springer Science+Business Media, LLC