A Role for CD103 in the Retention of CD4+CD25+ Treg and Control of Leishmania major Infection

Abstract

Endogenous regulatory T cells (Treg) play a central role in the control of excessive or misdirected immune responses against self or foreign Ags. To date, virtually no data are available on the nature of the molecules and signals involved in the trafficking and retention of Treg in tissues where regulation is required. Here, we show that expression of αEβ7 integrin is necessary for the homing of Treg at site of Leishmania major infection. The vast majority of Treg present in the dermis at steady-state conditions or during L. major infection express the αE chain (CD103) of αEβ7. Genetically susceptible BALB/c mice that lack CD103 become resistant to infection, a phenotype that is associated with a poor capacity of Treg to be retained in the infected site. Such susceptible phenotype can be restored when Treg from wild-type mice were transferred in CD103−/− mice. The central role of CD103 in Treg retention was further demonstrated by usage of blocking Abs against CD103 and the transfer of Treg purified from CD103−/− mice. Our results strongly suggest that this molecule is induced and maintained on Treg following or just prior to their arrival in tissues. Furthermore, the expression of CD103 and the subsequent retention of Treg in tissues is highly regulated by their exposure to Leishmania Ag and the level of activation of the APCs they encounter. Thus, CD103, by controlling Treg retention, can contribute to the outcome of chronic infection by Leishmania.

Systemic and Local Characterization of Regulatory T Cells in a Chronic Fungal Infection in Humans

“…Indeed, yeast cells were found in all biopsies studied (data not shown). In agreement with our findings, the CD4 ϩ CD25 ϩ T cells in L. majorinduced skin lesion (18,23,34,35), S. mansoni egg-induced granulomas (44), and Candida albicans (45) control effector immune response, allowing pathogen persistence. Thus, the enhanced expression and function of cells with a natural Treg phenotype in lesions of patients with PCM suggest this cell type to be a major contributor to parasite persistent and induction of chronicity.…”

“…We found that CD4 ϩ CD25 ϩ T cells expressing CTLA-4, GITR, CD45RO, LAP, and Foxp3 were present in P. brasiliensis-induced lesions. Aside from these markers, the majority of CD4 ϩ CD25 ϩ T cells also expressed CD103, CCR4, and CCR5, all of which are involved in Treg cell migration (24,25,(35)(36)(37). Therefore, the increased presence of CCL17, CCL22 (CCR4 ligands), and the CCL5 (CCR5 ligand) (Fig.…”

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

“…CD103 has been shown to be necessary for the retention of Tregs at inflamed sites of Leishmania major infection (22). In contrast, recent studies have shown that lack of CD103 has no effect on the absolute number of Tregs in the intestine in murine models of colitis and Trichuris infection (23).…”

Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection

“…8). It has recently been published that CD103 controls the retention of Treg in leishmania infection of the skin [28]. Knockout mice lacking the CD103 molecule showed no Treg activity during leishmania infection, underscoring the importance of CD103 for Treg functions.…”